Continuous analyte monitoring system with microneedle array

ABSTRACT

Described herein are variations of an analyte monitoring system, including an analyte monitoring device. For example, an analyte monitoring device may include an implantable microneedle array for use in measuring one or more analytes (e.g., glucose), such as in a continuous manner. The microneedle array may include, for example, at least one microneedle including a tapered distal portion having an insulated distal apex, and an electrode on a surface of the tapered distal portion located proximal to the insulated distal apex. At least some of the microneedles may be electrically isolated such that one or more electrodes is individually addressable.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/389,153, filed Jul. 29, 2021, which claims priority to U.S.Provisional Patent Application No. 63/058,275, filed Jul. 29, 2020, thecontents of each of which are hereby incorporated in their entirety bythis reference.

TECHNICAL FIELD

This invention relates generally to the field of analyte monitoring,such as continuous glucose monitoring.

BACKGROUND

Diabetes is a chronic disease in which the body does not produce orproperly utilize insulin, a hormone that regulates blood glucose.Insulin may be administered to a diabetic patient to help regulate bloodglucose levels, though blood glucose levels must nevertheless becarefully monitored to help ensure that timing and dosage areappropriate. Without proper management of their condition, diabeticpatients may suffer from a variety of complications resulting fromhyperglycemia (high blood sugar levels) or hypoglycemia (low blood sugarlevels).

Blood glucose monitors help diabetic patients manage their condition bymeasuring blood glucose levels from a sample of blood. For example, adiabetic patient may obtain a blood sample through a fingersticksampling mechanism, transfer the blood sample to a test strip withsuitable reagent(s) that react with the blood sample, and use a bloodglucose monitor to analyze the test strip to measure glucose level inthat blood sample. However, a patient using this process can typicallyonly measure his or her glucose levels at discrete instances in time,which may fail to capture a hyperglycemia or hypoglycemia condition in atimely manner. Yet a more recent variety of glucose monitor is acontinuous glucose monitor (CGM) device, which includes implantabletransdermal electrochemical sensors that are used to continuously detectand quantify blood glucose levels by proxy measurement of glucose levelsin the subcutaneous interstitial fluid. However, conventional CGMdevices also have weaknesses including tissue trauma from insertion andsignal latency (e.g., due to the time required for the glucose analyteto diffuse from capillary sources to the sensor). These weaknesses alsolead to a number of drawbacks, such as pain experienced by the patientwhen electrochemical sensors are inserted, and limited accuracy inglucose measurements, particularly when blood glucose levels arechanging rapidly. Accordingly, there is a need for a new and improvedanalyte monitoring system.

SUMMARY

In some variations, a microneedle array for use in sensing an analytemay include a plurality of microneedles (e.g., solid microneedles). Eachmicroneedle may include a tapered distal portion having an insulateddistal apex, and an electrode on a surface of the tapered distalportion, where the electrode is located proximal to the insulated distalapex.

In some variations, a method for monitoring a user may include accessinga body fluid of a user with an analyte monitoring device, andquantifying one or more analytes in the body fluid using the analytemonitoring device, where the analyte monitoring device may include aplurality of solid microneedles. In some variations, at least one of themicroneedles may include a tapered distal portion having an insulateddistal apex, and an electrode on a surface of the tapered distalportion, where the electrode is located proximal to the insulated distalapex.

In some variations, a microneedle array for use in sensing an analytemay include a plurality of solid microneedles, where at least onemicroneedle includes a tapered distal portion having an insulated distalapex, and an electrode on a surface of the tapered distal portion, wherea distal end of the electrode is offset from the distal apex.

In some variations, a method of sterilizing an analyte monitoring devicemay include exposing the analyte monitoring device to a sterilant gas,where the analyte monitoring device comprises a wearable housing, amicroneedle array extending from the housing and comprising an analytesensor, and an electronics system arranged in the housing andelectrically coupled to the microneedle array. The analyte monitoringdevice may be exposed to the sterilant gas for a dwell time sufficientto sterilize the analyte monitoring device.

In some variations, a microneedle array for an analyte monitoring devicemay include a plurality of sensing microneedles (e.g., solidmicroneedles), where each sensing microneedle includes a tapered distalportion comprising a working electrode configured to sense an analyte,and a body portion providing a conductive connection to the workingelectrode. The body portion of each sensing microneedle may be insulatedsuch that each working electrode is individually addressable andelectrically isolated from every other working electrode in themicroneedle array.

In some variations, a microneedle array for a body-worn analytemonitoring device may include at least one microneedle including apyramidal body portion having anon-circular (e.g., octagonal base), anda tapered distal portion extending from the body portion and comprisingan electrode, where the distal portion comprises a planar surface thatis offset from a distal apex of the at least one microneedle.

In some variations, a method for monitoring a user may include accessinga dermal interstitial fluid of the user at a plurality of sensorlocations with an integrated analyte monitoring device comprising asingle microneedle array, and quantifying one or more analytes in thedermal interstitial fluid using a plurality of working electrodes in themicroneedle array, where each working electrode is individuallyaddressable and electrically isolated from every other working electrodein the analyte monitoring device.

In some variations, a body-worn analyte monitoring device may include awearable housing and a microneedle array. The microneedle array mayextend outwardly from the housing and include at least one microneedleconfigured to measure one or more analytes in a user wearing thehousing, and the housing may include a user interface configured tocommunicate information indicative of the measurement of the one or moreanalytes.

In some variations, a method for monitoring a user may include measuringone or more analytes in the user using a body-worn analyte monitoringdevice comprising a wearable housing and one or more analyte sensors,and communicating information indicative of the measurement of the oneor more analytes through a user interface on the housing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an illustrative schematic of an analyte monitoring systemwith a microneedle array.

FIG. 2A depicts an illustrative schematic of an analyte monitoringdevice.

FIG. 2B depicts an illustrative schematic of microneedle insertion depthin an analyte monitoring device.

FIGS. 3A-3C depict an upper perspective view, a side view, and a lowerperspective view, respectively, of an analyte monitoring device. FIG. 3Ddepicts a partially exploded view of the analyte monitoring device shownin FIG. 3A including an adhesive layer. FIG. 3E depicts an exploded viewof the analyte monitoring device shown in FIG. 3A.

FIGS. 3F-3I depict an upper perspective view, a lower perspective view,a side view, and an exploded view, respectively, of a sensor assembly inan analyte monitoring device.

FIG. 3J depicts a transparent side view of a sensor assembly in ananalyte monitoring device.

FIGS. 4A-4E depict a perspective view, a side view, a bottom view, aside cross-sectional view, and an upper perspective transparent view,respectively, of an analyte monitoring device.

FIG. 5A depicts an illustrative schematic of a microneedle array. FIG.5B depicts an illustrative schematic of a microneedle in the microneedlearray depicted in FIG. 5A.

FIG. 6 depicts an illustrative schematic of a microneedle array used forsensing multiple analytes.

FIG. 7A depicts a cross-sectional side view of a columnar microneedlehaving a tapered distal end. FIGS. 7B and 7C are images depictingperspective and detailed views, respectively, of an embodiment of themicroneedle shown in FIG. 7A.

FIG. 8 depicts an illustrative schematic of a columnar microneedlehaving a tapered distal end.

FIG. 9 depicts a cross-sectional side view of a columnar microneedlehaving a tapered distal end.

FIG. 10 depicts an illustrative schematic of a columnar microneedlehaving a tapered distal end.

FIG. 11A depicts a cross-sectional side view of a pyramidal microneedlehaving a tapered distal end. FIG. 11B is an image depicting aperspective view of an embodiment of the microneedle shown in FIG. 11A.FIG. 11C is an image depicting an illustrative variation of amicroneedle array including microneedles similar to that shown in FIG.11B.

FIG. 12 depicts an illustrative schematic of a pyramidal microneedlehaving a tapered distal end.

FIG. 13A depicts an illustrative schematic of a pyramidal microneedlehaving a tapered distal end and asymmetric cut surface. FIG. 13B is animage depicting an illustrative variation of the microneedle shown inFIG. 13A.

FIGS. 13C-13E illustrate a process for forming the pyramidal microneedleshown in FIG. 13A.

FIG. 14A depicts an illustrative schematic of a columnar-pyramidalmicroneedle having a tapered distal end. FIG. 14B depicts a detailedview of the distal portion of the microneedle depicted in FIG. 14A.

FIGS. 15A-15D depict illustrative schematics of formation of conductivepathways within a microneedle array.

FIGS. 16A-16C depict illustrative schematics of layered structures of aworking electrode, a counter electrode, and a reference electrode,respectively.

FIGS. 16D-16F depict illustrative schematics of layered structures of aworking electrode, a counter electrode, and a reference electrode,respectively.

FIGS. 16G-16I depict illustrative schematics of layered structures of aworking electrode, a counter electrode, and a reference electrode,respectively.

FIG. 17 depicts an illustrative schematic of a microneedle arrayconfiguration.

FIGS. 18A and 18B depict perspective and orthogonal views, respectively,of an illustrative variation of a die including a microneedle array.

FIGS. 19A-19J depict illustrative schematics of different variations ofmicroneedle array configurations.

FIG. 20 depicts an illustrative schematic of a low profile batteryholder.

FIG. 21 depicts an illustrative flowchart of a method for sterilizing ananalyte monitoring device.

FIG. 22 depicts an illustrative schematic of a sterilization setupusable for ethylene oxide sterilization.

FIG. 23 depicts an illustrative variation of an ethylene oxidesterilization protocol.

FIGS. 24A-24C depict exemplary data suggesting feasibility of ethyleneoxide sterilization for an analyte monitoring device.

FIG. 25 is an illustrative schematic of electronic circuitry enablingactivation of an analyte monitoring device upon insertion of themicroneedle array in skin.

FIG. 26 is an illustrative schematic of pairing between an analytemonitoring device and a mobile computing device executing a mobileapplication.

FIGS. 27A and 27B depict illustrative schematics of a microneedle arrayand a microneedle, respectively. FIGS. 27C-27F depict detailed partialviews of an illustrative variation of a microneedle.

FIGS. 28A and 28B depict an illustrative variation of a microneedle.

FIGS. 29A and 29B depict illustrative schematics of a microneedle arrayconfiguration.

FIGS. 30A and 30B depict illustrative schematics of a microneedle arrayconfiguration.

FIGS. 31A and 31B depict illustrative schematics of a housing of ananalyte monitoring device including a user interface with indicatorlight elements.

FIGS. 32A-32C depict illustrative schematics of illumination modes in ananalyte monitoring device for indicating analyte measurement data.

FIGS. 33A-33D depict illustrative schematics of illumination modes in ananalyte monitoring device for indicating analyte measurement data.

FIGS. 34A-34C depict illustrative schematics of illumination modes in ananalyte monitoring device for indicating analyte measurement data.

FIGS. 35A and 35B depict illustrative schematics of illumination modesin an analyte monitoring device for indicating device information (e.g.,operational status, and/or fault modes).

DETAILED DESCRIPTION

Non-limiting examples of various aspects and variations of the inventionare described herein and illustrated in the accompanying drawings.

As generally described herein, an analyte monitoring system may includean analyte monitoring device that is worn by a user and includes one ormore sensors for monitoring at least one analyte of a user. The sensorsmay, for example, include one or more electrodes configured to performelectrochemical detection of at least one analyte. The analytemonitoring device may communicate sensor data to an external computingdevice for storage, display, and/or analysis of sensor data. Forexample, as shown in FIG. 1 , an analyte monitoring system 100 mayinclude an analyte monitoring device 110 that is worn by a user, and theanalyte monitoring device 110 may be a continuous analyte monitoringdevice (e.g., continuous glucose monitoring device). The analytemonitoring device 110 may include, for example, a microneedle arraycomprising at least one electrochemical sensor for detecting and/ormeasuring one or more analytes in body fluid of a user. In somevariations, the analyte monitoring device may be applied to the userusing suitable applicator 160, or may be applied manually. The analytemonitoring device 110 may include one or more processors for performinganalysis on sensor data, and/or a communication module (e.g., wirelesscommunication module) configured to communicate sensor data to a mobilecomputing device 102 (e.g., smartphone) or other suitable computingdevice. In some variations, the mobile computing device 102 may includeone or more processors executing a mobile application to handle sensordata (e.g., displaying data, analyzing data for trends, etc.) and/orprovide suitable alerts or other notifications related to the sensordata and/or analysis thereof. It should be understood that while in somevariations the mobile computing device 102 may perform sensor dataanalysis locally, other computing device(s) may alternatively oradditionally remotely analyze sensor data and/or communicate informationrelated to such analysis with the mobile computing device 102 (or othersuitable user interface) for display to the user. Furthermore, in somevariations the mobile computing device 102 may be configured tocommunicate sensor data and/or analysis of the sensor data over anetwork 104 to one or more storage devices 106 (e.g., server) forarchiving data and/or other suitable information related to the user ofthe analyte monitoring device.

The analyte monitoring devices described herein have characteristicsthat improve a number of properties that are advantageous for acontinuous analyte monitoring device such as a continuous glucosemonitoring (CGM) device. For example, the analyte monitoring devicedescribed herein have improved sensitivity (amount of sensor signalproduced per given concentration of target analyte), improvedselectivity (rejection of endogenous and exogenous circulating compoundsthat can interfere with the detection of the target analyte), andimproved stability to help minimize change in sensor response over timethrough storage and operation of the analyte monitoring device.Additionally, compared to conventional continuous analyte monitoringdevices, the analyte monitoring devices described herein have a shorterwarm-up time that enables the sensor(s) to quickly provide a stablesensor signal following implantation, as well as a short response timethat enables the sensors(s) to quickly provide a stable sensor signalfollowing a change in analyte concentration in the user. Furthermore, asdescribed in further detail below, the analyte monitoring devicesdescribed herein may be applied to and function in a variety of wearsites, and provide for pain-free sensor insertion for the user. Otherproperties such as biocompatibility, sterilizability, and mechanicalintegrity are also optimized in the analyte monitoring devices describedherein.

Although the analyte monitoring systems described herein may bedescribed with reference to monitoring of glucose (e.g., in users withType 2 diabetes, Type 1 diabetes), it should be understood that suchsystems may additionally or alternatively be configured to sense andmonitor other suitable analytes. As described in further detail below,suitable target analytes for detection may, for example, includeglucose, ketones, lactate, and cortisol. One target analyte may bemonitored, or multiple target analytes may be simultaneously monitored(e.g., in the same analyte monitoring device). For example, monitoringof other target analytes may enable the monitoring of other indicationssuch as stress (e.g., through detection of rising cortisol and glucose)and ketoacidosis (e.g., through detection of rising ketones).

Various aspects of example variations of the analyte monitoring systems,and methods of use thereof, are described in further detail below.

Analyte Monitoring Device

As shown in FIG. 2A, in some variations, an analyte monitoring device110 may generally include a housing 112 and a microneedle array 140extending outwardly from the housing. The housing 112, may, for example,be a wearable housing configured to be worn on the skin of a user suchthat the microneedle array 140 extends at least partially into the skinof the user. For example, the housing 112 may include an adhesive suchthat the analyte monitoring device 110 is a skin-adhered patch that issimple and straightforward for application to a user. The microneedlearray 140 may be configured to puncture the skin of the user and includeone or more electrochemical sensors (e.g., electrodes) configured formeasuring one or more target analytes that are accessible after themicroneedle array 140 punctures the skin of the user. In somevariations, the analyte monitoring device 110 may be integrated orself-contained as a single unit, and the unit may be disposable (e.g.,used for a period of time and replaced with another instance of theanalyte monitoring device 110).

An electronics system 120 may be at least partially arranged in thehousing 112 and include various electronic components, such as sensorcircuitry 124 configured to perform signal processing (e.g., biasing andreadout of electrochemical sensors, converting the analog signals fromthe electrochemical sensors to digital signals, etc.). The electronicssystem 120 may also include at least one microcontroller 122 forcontrolling the analyte monitoring device 110, at least onecommunication module 126, at least one power source 130, and/or othervarious suitable passive circuitry 127. The microcontroller 122 may, forexample, be configured to interpret digital signals output from thesensor circuitry 124 (e.g., by executing a programmed routine infirmware), perform various suitable algorithms or mathematicaltransformations (e.g., calibration, etc.), and/or route processed datato and/or from the communication module 124. In some variations, thecommunication module 126 may include a suitable wireless transceiver(e.g., Bluetooth transceiver or the like) for communicating data with anexternal computing device 102 via one or more antennas 128. For example,the communication module 126 may be configured to provideuni-directional and/or bi-directional communication of data with anexternal computing device 102 that is paired with the analyte monitoringdevice 110. The power source 130 may provide power for the analytemonitoring device 110, such as for the electronics system. The powersource 130 may include battery or other suitable source, and may, insome variations, be rechargeable and/or replaceable. Passive circuitry127 may include various non-powered electrical circuitry (e.g.,resistors, capacitors, inductors, etc.) providing interconnectionsbetween other electronic components, etc. The passive circuitry 127 maybe configured to perform noise reduction, biasing and/or other purposes,for example. In some variations, the electronic components in theelectronics system 120 may be arranged on one or more printed circuitboards (PCB), which may be rigid, semi-rigid, or flexible, for example.Additional details of the electronics system 120 are described furtherbelow.

In some variations, the analyte monitoring device 110 may furtherinclude one or more additional sensors 150 to provide additionalinformation that may be relevant for user monitoring. For example, theanalyte monitoring device 110 may further include at least onetemperature sensor (e.g., thermistor) configured to measure skintemperature, thereby enabling temperature compensation for the sensormeasurements obtained by the microneedle array electrochemical sensors.

In some variations, the microneedle array 140 in the analyte monitoringdevice 110 may be configured to puncture skin of a user. As shown inFIG. 2B, when the device 110 is worn by the user, the microneedle array140 may extend into the skin of the user such that electrodes on distalregions of the microneedles rest in the dermis. Specifically, in somevariations, the microneedles may be designed to penetrate the skin andaccess the upper dermal region (e.g., papillary dermis and upperreticular dermis layers) of the skin, in order to enable the electrodesto access interstitial fluid that surrounds the cells in these layers.For example, in some variations, the microneedles may have a heightgenerally ranging between at least 350 μm and about 515 μm. In somevariations, one or more microneedles may extend from the housing suchthat a distal end of the electrode on the microneedle is located lessthan about 5 mm from a skin-interfacing surface of the housing, lessthan about 4 mm from the housing, less than about 3 mm from the housing,less than about 2 mm from the housing, or less than about 1 mm from thehousing.

In contrast to traditional continuous analyte monitoring devices (e.g.,CGM devices), which include sensors typically implanted between about 8mm and about 10 mm beneath the skin surface in the subcutis or adiposelayer of the skin, the analyte monitoring device 110 has a shallowermicroneedle insertion depth of about 0.25 mm (such that electrodes areimplanted in the upper dermal region of the skin) that provides numerousbenefits. These benefits include access to dermal interstitial fluidincluding one or more target analytes for detection, which isadvantageous at least because at least some types of analytemeasurements of dermal interstitial fluid have been found to closelycorrelate to those of blood. For example, it has been discovered thatglucose measurements performed using electrochemical sensors accessingdermal interstitial fluid are advantageously highly linearly correlatedwith blood glucose measurements. Accordingly, glucose measurements basedon dermal interstitial fluid are highly representative of blood glucosemeasurements.

Additionally, because of the shallower microneedle insertion depth ofthe analyte monitoring device 110, a reduced time delay in analytedetection is obtained compared to traditional continuous analytemonitoring devices. Such a shallower insertion depth positions thesensor surfaces in close proximity (e.g., within a few hundredmicrometers or less) to the dense and well-perfused capillary bed of thereticular dermis, resulting in a negligible diffusional lag from thecapillaries to the sensor surface. Diffusion time is related todiffusion distance according to t=x²/(2D) where t is the diffusion time,x is the diffusion distance, and D is the mass diffusivity of theanalyte of interest. Therefore, positioning an analyte sensing elementtwice as far away from the source of an analyte in a capillary willresult in a quadrupling of the diffusional delay time. Accordingly,conventional analyte sensors, which reside in the very poorlyvascularized adipose tissue beneath the dermis, result in asignificantly greater diffusion distance from the vasculature in thedermis and thus a substantial diffusional latency (e.g., typically 5-20minutes). In contrast, the shallower microneedle insertion depth of theanalyte monitoring device 110 benefits from low diffusional latency fromcapillaries to the sensor, thereby reducing time delay in analytedetection and providing more accurate results in real-time or nearreal-time. For example, in some embodiments, diffusional latency may beless than 10 minutes, less than 5 minutes, or less than 3 minutes.

Furthermore, when the microneedle array rests in the upper dermalregion, the lower dermis beneath the microneedle array includes veryhigh levels of vascularization and perfusion to support the dermalmetabolism, which enables thermoregulation (via vasoconstriction and/orvasodilation) and provides a barrier function to help stabilize thesensing environment around the microneedles. Yet another advantage ofthe shallower insertion depth is that the upper dermal layers lack painreceptors, thus resulting in a reduced pain sensation when themicroneedle array punctures the skin of the user, and providing for amore comfortable, minimally-invasive user experience.

Thus, the analyte monitoring devices and methods described herein enableimproved continuous monitoring of one or more target analytes of a user.For example, as described above, the analyte monitoring device may besimple and straightforward to apply, which improves ease-of-use and usercompliance. Additionally, analyte measurements of dermal interstitialfluid may provide for highly accurate analyte detection. Furthermore,compared to traditional continuous analyte monitoring devices, insertionof the microneedle array and its sensors may be less invasive andinvolve less pain for the user. Additional advantages of other aspectsof the analyte monitoring devices and methods are further describedbelow.

Housing

As described above, an analyte monitoring device may include a housing.The housing may at least partially surround or enclose other componentsof the analyte monitoring device (e.g., electronic components), such asfor protection of such components. For example, the housing may beconfigured to help prevent dust and moisture from entering the analytemonitoring device. In some variations, an adhesive layer may attach thehousing to a surface (e.g., skin) of a user, while permitting amicroneedle array to extend outwardly from the housing and into the skinof the user. Furthermore, in some variations the housing may generallyinclude rounded edges or corners and/or be low-profile so as to beatraumatic and reduce interference with clothing, etc. worn by the user.

For example, as shown in FIGS. 3A-3E, an example variation of an analytemonitoring device 300 may include a housing 310 configured to at leastpartially surround other various internal components of the device 300,and a microneedle array 330 that extends outwardly from a skin-facingsurface (e.g., underside) of the housing 310.

The housing 310 may, for example, include one or more rigid orsemi-rigid protective shell components that may couple together viasuitable fasteners (e.g., mechanical fasteners), mechanicallyinterlocking or mating features, and/or an engineering fit. For example,as shown in FIG. 3E, the housing may include a housing cover 310 a and ahousing base 310 b, where the cover 310 a and the base 310 b may besecured together with one or more threaded fasteners (e.g., fastenersthat engage threaded holes in the upper and/or lower housing portions).The cover 310 a and the base 310 b may include radiused edges andcorners, and/or other atraumatic features. When coupled together, thecover 310 a and the base 310 b may form an internal volume that housesother internal components such as a device printed circuit board 350(PCB), a sensor assembly 320, and/or other components such as a gasket312. For example, the internal components arranged in the internalvolume may be arranged in a compact, low profile stack-up as shown inFIG. 3E. While FIG. 3E illustrates a housing 310 include multiplehousing components, in some variations the housing 310 may include asingle component defining the internal volume for housing internaldevice components. In some embodiments, the housing 310 may be filledwith a suitable potting compound (e.g., epoxy) to reduce deleteriousenvironmental effects such as temperature, humidity, pressure, andlight.

Furthermore, the analyte monitoring device 300 may include an adhesivelayer 340 configured to attach the housing 310 to a surface (e.g., skin)of a user. The adhesive layer 340 may, for example, be attached to askin-facing side of the housing 310 via a double-sided adhesive liner344 as shown in in the variation depicted in FIG. 3D. Alternatively, theadhesive layer 340 may be coupled directly to the skin-facing side ofthe housing 310 with one or more suitable fasteners (e.g., adhesive,mechanical fasteners, etc.). The adhesive layer 340 may be protected bya release liner that the user removes prior to skin application, inorder to expose the adhesive. In some variations, the analyte monitoringdevice may include 3M® 1504XL™ double-sided adhesive and 3M® 4076™skin-facing adhesive, available from 3M®. These materials are selectedfor their: breathability, wearability, mean water vapor transmissionrate (MWVTR), biocompatibility, compatibility with sensor sterilizationmethod/strategy, appearance, durability, tackiness, and ability toretain said tackiness for the duration of sensor wear.

The adhesive layer 340 may, in some variations, have a perimeter thatextends farther than the perimeter or periphery of the housing 310(e.g., which may increase surface area for attachment and increasestability of retention, or the attachment to the skin of a user).Furthermore, in some variations, the adhesive layer 340 may include anopening 342 that permits passage of the outwardly extending microneedlearray 330. The opening 342 may closely circumscribe the shape of themicroneedle array 330 as shown in FIG. 3C (e.g., square opening closelycorresponding in size and shape to a square microneedle array), or haveanother suitable size and shape that is larger than the footprint areaof the microneedle array (e.g., circular opening larger than a squaremicroneedle array).

Although the housing 310 depicted in FIGS. 3A-3E is hexagonal shaped andgenerally prismatic, it should be understood that in other variations,the housing 310 may have any suitable shape. For example, in othervariations the housing may be generally prismatic and have a base thathas an elliptical (e.g., circular), triangular, rectangular, pentagonal,or other suitable shape. As another example, FIGS. 4A-4C illustrate anexample variation of an analyte monitoring device 400 including adome-shaped housing 410. While the dome-shaped housing 410 depicted inFIGS. 4A-4C is generally circular, in other variations the dome-shapedhousing may have a base that has another suitable elliptical shape orpolygonal shape.

Similar to the housing 310, the housing 410 may include an internalvolume configured to at least partially surround other components of theanalyte monitoring device 400. For example, as shown in thecross-sectional view of FIG. 4D, the housing 410 may include a domedcover 410 a coupled to a base 410 b, so as to form an internal volumewithin which a device PCB 450 and a sensor assembly with a microneedlearray 430 may be arranged. Additionally, the housing 410 may beconfigured to couple to a surface via an adhesive layer 440, and themicroneedle array 430 may extend outwardly from the housing and beyondthe adhesive layer 440. Furthermore, as shown in FIGS. 4D and 4E, theadhesive layer 440 may extend beyond the perimeter of the housing 410.

User Interface

In some variations, an analyte monitoring system may provide userstatus, analyte monitoring device status, and/or other suitableinformation directly via a user interface (e.g., display, indicatorlights, etc. as described below) on the analyte monitoring device. Thus,in contrast to analyte monitoring systems that may solely communicateinformation to a separate peripheral device (e.g., mobile phone, etc.)that in turn communicates the information to a user, in some variationssuch information may be directly provided by the analyte monitoringdevice. Advantageously, in some variations, such a user interface on theanalyte monitoring device may reduce the need for a user to constantlymaintain a separate peripheral device in order to monitor user statusand/or analyte monitoring device status (which may be impractical due tocost, inconvenience, etc.). Additionally, the user interface on theanalyte monitoring device may reduce risks associated with loss ofcommunication between the analyte monitoring device and a separateperipheral device, such as a user having an inaccurate understanding oftheir current analyte levels (e.g., leading the user to assume theiranalyte levels are high when they are actually low, which could, forexample, result in the user self-administering an inaccurate dose ofdrug or withholding a therapeutic intervention when it is medicallynecessary).

Additionally, the ability to communicate information to a user via theanalyte monitoring device itself, independently of a separate peripheraldevice, may reduce or eliminate the need to maintain compatibilitybetween the analyte monitoring device and separate peripheral devices assuch peripheral devices are upgraded (e.g., replaced with new devicemodels or other hardware, run new versions of operating systems or othersoftware, etc.).

Accordingly, in some variations, the housing may include a userinterface, such as an interface to provide information in a visual,audible, and/or tactile manner to provide information regarding userstatus and/or status of the analyte monitoring device, and/or othersuitable information. Examples of user status that may be communicatedvia the user interface include information representative of analytemeasurement in the user (e.g., below a predetermined target analytemeasurement threshold or range, within a predetermined target analytemeasurement range, above a predetermined target analyte measurementthreshold or range, increase or decrease of analyte measurement overtime, rate of change of analyte measurement, other information relatingto trend of analyte measurements, other suitable alerts associated withanalyte measurement, etc.). Examples of analyte monitoring device statusthat may be communicated via the user interface include device operationmode (e.g., associated with device warm-up state, analyte monitoringstate, battery power status such as low battery, etc.), a device errorstate (e.g., operational error, pressure-induced sensing attenuation,fault, failure mode, etc.), device power status, device life status(e.g., anticipated sensor end-of-life), status of connectivity betweendevice and a mobile computing device, and/or the like.

In some variations, the user interface may by default be in an enabledor “on” state to communicate such information at least whenever theanalyte monitoring device is performing analyte measurements) orwhenever the analyte monitoring device is powered on, thereby helping toensure that information is continuously available to the user. Forexample, user interface elements may communicate through a display orindicator light(s) (e.g., as described below) not only alerts to flaguser attention or recommend remedial action, but also when user statusand/or device status are normal. Accordingly, in some variations, a useris not required to perform an action to initiate a scan to learn theircurrent analyte measurement level(s), and such information may alwaysreadily be available to the user. In some variations, however, a usermay perform an action to disable the user interface temporarily (e.g.,similar to a “snooze” button) such as for a predetermined amount of time(e.g., 30 minutes, 1 hour, 2 hours, etc.) after which the user interfaceis automatically reenabled, or until a second action is performed toreenable the user interface.

In some variations, the user interface of the housing may include adisplay configured to visually communicate information. The display may,for example, include a display screen (e.g., LCD screen, OLED display,electrophoretic display, electrochromic display, etc.) configured todisplay alphanumeric text (e.g., numbers, letters, etc.), symbols,and/or suitable graphics to communicate information to the user. Forexample, the display screen may include a numerical information, textualinformation, and/or a graphics (e.g., sloped line, arrows, etc.) ofinformation such as user status and/or status of the analyte monitoringdevice. For example, the display screen may include text or graphicalrepresentations of analyte measurement levels, trends, and/orrecommendations (e.g., physical activity, reduced dietary intake, etc.).

As another example, the display on the housing may include one or moreindicator lights (e.g., including LEDs, OLEDs, lasers,electroluminescent material, or other suitable light source, waveguides,etc.) that may be controlled in one or more predetermined illuminationmodes to communicate different statuses and/or other suitableinformation. An indicator light may be controlled to illuminate withmultiple colors (e.g., red, orange, yellow, green, blue, and/or purple,etc.) or in only one color. For example, an indicator light may includea multi-colored LED. As another example, an indicator light may includea transparent or semi-transparent material (e.g., acrylic) positionedover one or more different-colored light sources (e.g., LED) such thatdifferent-colored light sources may be selectively activated toilluminate the indicator light in a selected color. The activation oflight sources can either occur simultaneously or in sequence. Anindicator light may have any suitable form (e.g., raised, flush,recessed, etc. from housing body) and/or shape (e.g., circle or otherpolygon, ring, elongated strip, etc.). In some variations, an indicatorlight may have a pinhole size and/or shape to present the same intensityof the light as a larger light source, but with significantly less powerrequirements, which may help conserve onboard power in the analytemonitoring device.

Indicator light(s) on the display may be illuminated in one or morevarious manners to communicate different kinds of information. Forexample, an indicator light may be selectively illuminated on or off tocommunicate information (e.g., illumination “on” indicates one status,while illumination “off” indicates another status). Additionally oralternatively, an indicator light may be illuminated in a selected coloror intensity to communicate information (e.g., illumination in a firstcolor or intensity indicates a first status, while illumination in asecond color or intensity indicates a second status). Additionally oralternatively, an indicator light may be illuminated in a selectedtemporal pattern to communicate information (e.g., illumination in afirst temporal pattern indicates a first status, while illumination in asecond temporal pattern indicates a second status). For example, anindicator light may be selectively illuminated in one of a plurality ofpredetermined temporal patterns that differ in illumination frequency(e.g., repeated illumination at a rapid or slow frequency), regularity(e.g., periodic repeated illumination vs. intermittent illumination),duration of illumination “on” time, duration of illumination “off” time,rate of change in illumination intensity, duty cycle (e.g., ratio ofillumination “on” time to illumination “off” time), and/or the like,where each predetermined temporal pattern may indicate a respectivestatus.

Additionally or alternatively, in some variations, a display may includemultiple indicator lights that may be collectively illuminated in one ormore predetermined illumination modes or sequences in accordance withone or more predetermined spatial and/or temporal patterns. For example,in some variations, some or all of the indicator lights arranged on adisplay may be illuminated in synchrony or in sequence to indicate aparticular status. Accordingly, the selected subset of indicator lights(e.g., the spatial arrangement of the indicator lights that areilluminated) and/or the manner in which they are illuminated (e.g.,illumination order, illumination rate, etc.) may indicate a particularstatus. Additionally or alternatively, a plurality of indicator lightsmay illuminate simultaneously or in sequence to increase the diversityof the color palette. For example, in some variations, red, green, andblue LEDs may be illuminated in rapid succession to create theimpression of white light to a user.

It should furthermore be understood that one or more of theabove-described illumination modes may be combined in any suitablemanner (e.g., combination of varying color, intensity, brightness,luminosity, contrast, timing, location, etc.) to communicateinformation. Additionally or alternatively, an ambient light sensor maybe incorporated into the device body to enable dynamic adjustment lightlevels in the indicator light(s) to compensate for environmental lightconditions to help conserve power. The ambient light sensor may, in somevariations, be used in conjunction with a kinetic sensor (e.g., asdescribed in further detail below) to further determine appropriateperiods for the analyte monitoring device to enter into a power savingmode or reduced power state. For example, detection of darkness and nomotion of the analyte monitoring device may indicate that the wearer ofthe analyte monitoring device is asleep, which may trigger the analytemonitoring device to enter into a power saving mode or reduced powerstate.

FIG. 31A illustrates an example variation of an analyte monitoringdevice 3100 including a user interface 3120 with multiple indicatorlights (3122, 3124 a-3124 c). Indicator light 3120 may, for example, beselectively illuminated to indicate a device state (e.g., operationmode, error state, power status, life status, etc.). Although indicatorlight 3122 is in the shape of a symbol (e.g., logo), it should beunderstood that in other variations, the indicator light 3122 may haveany suitable shape (e.g., text, other geometric shape, etc.). Indicatorlights 3124 a-3124 c may be selectively illuminated to indicate a userstatus (e.g., information representative of analyte measurement).Although indicator lights 3124 a-3124 c are linear elements extendingacross the user interface (e.g., chords across a circular display), itshould be understood that in other variations, the indicator lights 3124a-3124 c have other suitable shapes (e.g., wavy lines, circular, etc.).In some variations, a 1-dimensional array of indicator lights of anysuitable shape may be arranged on the housing (e.g., arranged in a row,a column, an arc, etc.). Alternatively, the housing may include amulti-dimensional array of indicator lights of any suitable shape.

Furthermore, in some variations, an indicator light may include an icon(e.g., symbol) that may be indicative of analyte information (e.g., uparrow to indicate rising analyte measurement level trend, down arrow toindicate falling analyte measurement level trend), analyte monitoringdevice status (e.g., exclamation point to indicate a device errorstate), and/or other suitable information. Additionally oralternatively, iconography in the indicator light(s) may be used tocommunicate recommendations for the user such as behavioralrecommendations. Iconography may, for example, have the advantage ofcommunicating recommendations to a user in a more universal orlanguage-agnostic manner (e.g., without the need for languagetranslations to tailor the device to different geographical regions oruser preferences, etc.). For example, as shown in FIG. 31B, in somevariations, in the context of glucose monitoring, a user interface foran analyte monitoring device 3100′ may include a running person icon3126 to indicate a recommendation that the user engage in physicalactivity. As another example, a food icon 3128 may indicate arecommendation that the user consume food (or in combination with an “X”icon 3130, to indicate a recommendation that the user restrict food). Asanother example, a drink icon 3132 may indicate a recommendation thatthe user consume fluid such as water (or in combination with an “X” icon3134, to indicate a recommendation that the user restrict fluid). Asanother example, a star icon 3136 may indicate positive reinforcement(e.g., indicating success in analyte measurement levels staying within anormal or target range for a predetermined period of time). However, itshould be understood that behavioral recommendations may vary based onthe indication relating to the analyte(s) being monitored. For example,in some variations in which the analyte monitoring device isadditionally or alternatively used to monitor cortisol, rising cortisollevels (and/or rising glucose levels) may be correlated to an increasein user stress. Accordingly, in some of these variations the analytemonitoring device may include a suitable icon to indicate arecommendation to the user to reduce exposure to stressors, to meditate,etc. to avoid implicating adverse health effects due to stress.

In the variations shown in FIGS. 31A and 31B, each of the indicatorlights 3124 a-3124 c may be exclusively illuminated to indicate adifferent analyte measurement (e.g., in target range, below targetrange, significantly below target range, above target range,significantly above target range, etc.). Furthermore, the indicatorlights 3124 a-3124 c may be arranged adjacent to each other, such thatthey may be selectively illuminated in a progressive sequence tocommunicate trend information of analyte measurements (e.g., progressivesequence of illumination in a first direction that corresponds to anincrease in measured quantity of an analyte, progressive sequence ofillumination in a second direction that corresponds to a decrease inmeasured quantity of an analyte, pace of illumination progression in thefirst direction or the second direction that corresponds to a rate ofincrease or decrease in measured quantity of an analyte, etc.). Anexample of such progressive sequence of illumination is furtherdescribed below with reference to FIGS. 33A-33D. While one device statusindicator light 3120 and three user status indicator lights 3124 a-3124c are shown in FIGS. 31A and 31B, it should be understood that in othervariations, an analyte monitoring device may include any suitable numberof indicator lights, such as one, two, three, four, five or more devicestatus indicator lights, and one, two, three, four, five or more userstatus indicator lights. Further details regarding an example operationof the user interface 3120 to communicate device status and/or userstatus are described below (e.g., with reference to FIGS. 32A-32C,33A-33D, 34A-34C, and 35A-35B).

Microneedle Array

As shown in the schematic of FIG. 5A, in some variations, a microneedlearray 510 for use in sensing one or more analytes may include one ormore microneedles 510 projecting from a substrate surface 502. Thesubstrate surface 502 may, for example, be generally planar and one ormore microneedles 510 may project orthogonally from the planar surface.Generally, as shown in FIG. 5B, a microneedle 510 may include a bodyportion 512 (e.g., shaft) and a tapered distal portion 514 configured topuncture skin of a user. In some variations, the tapered distal portion514 may terminate in an insulated distal apex 516. The microneedle 510may further include an electrode 520 on a surface of the tapered distalportion. In some variations, electrode-based measurements may beperformed at the interface of the electrode and interstitial fluidlocated within the body (e.g., on an outer surface of the overallmicroneedle). In some variations, the microneedle 510 may have a solidcore (e.g., solid body portion), though in some variations themicroneedle 510 may include one or more lumens, which may be used fordrug delivery or sampling of the dermal interstitial fluid, for example.Other microneedle variations, such as those described below, maysimilarly either include a solid core or one or more lumens.

The microneedle array 500 may be at least partially formed from asemiconductor (e.g., silicon) substrate and include various materiallayers applied and shaped using various suitable microelectromechanicalsystems (MEMS) manufacturing techniques (e.g., deposition and etchingtechniques), as further described below. The microneedle array may bereflow-soldered to a circuit board, similar to a typical integratedcircuit. Furthermore, in some variations the microneedle array 500 mayinclude a three electrode setup including a working (sensing) electrodehaving an electrochemical sensing coating (including a biorecognitionelement such as an enzyme) that enables detection of a target analyte, areference electrode, and a counter electrode. In other words, themicroneedle array 500 may include at least one microneedle 510 thatincludes a working electrode, at least one microneedle 510 including areference electrode, and at least one microneedle 510 including acounter electrode. Additional details of these types of electrodes aredescribed in further detail below.

In some variations, the microneedle array 500 may include a plurality ofmicroneedles that are insulated such that the electrode on eachmicroneedle in the plurality of microneedles is individually addressableand electrically isolated from every other electrode on the microneedlearray. The resulting individual addressability of the microneedle array500 may enable greater control over each electrode's function, sinceeach electrode may be separately probed. For example, the microneedlearray 500 may be used to provide multiple independent measurements of agiven target analyte, which improves the device's sensing reliabilityand accuracy. Furthermore, in some variations the electrodes of multiplemicroneedles may be electrically connected to produce augmented signallevels. As another example, the same microneedle array 500 mayadditionally or alternatively be interrogated to simultaneously measuremultiple analytes to provide a more comprehensive assessment ofphysiological status. For example, as shown in the schematic of FIG. 6 ,a microneedle array may include a portion of microneedles to detect afirst Analyte A, a second portion of microneedles to detect a secondAnalyte B, and a third portion of microneedles to detect a third AnalyteC. It should be understood that the microneedle array may be configuredto detect any suitable number of analytes (e.g., 1, 2, 3, 4, 5 or more,etc.). Suitable target analytes for detection may, for example, includeglucose, ketones, lactate, and cortisol. For example, in somevariations, ketones may be detected in a manner similar to thatdescribed in U.S. patent application Ser. No. 16/701,784, which isincorporated herein in its entirety by this reference. Thus, individualelectrical addressability of the microneedle array 500 provides greatercontrol and flexibility over the sensing function of the analytemonitoring device.

In some variations of microneedles (e.g., microneedles with a workingelectrode), the electrode 520 may be located proximal to the insulateddistal apex 516 of the microneedle. In other words, in some variationsthe electrode 520 does not cover the apex of the microneedle. Rather,the electrode 520 may be offset from the apex or tip of the microneedle.The electrode 520 being proximal to or offset from the insulated distalapex 516 of the microneedle advantageously provides more accurate sensormeasurements. For example, this arrangement prevents concentration ofthe electric field at the microneedle apex 516 during manufacturing,thereby avoiding non-uniform electro-deposition of sensing chemistry onthe electrode surface 520 that would result in faulty sensing.

As another example, placing the electrode 520 offset from themicroneedle apex further improves sensing accuracy by reducingundesirable signal artefacts and/or erroneous sensor readings caused bystress upon microneedle insertion. The distal apex of the microneedle isthe first region to penetrate into the skin, and thus experiences themost stress caused by the mechanical shear phenomena accompanying thetearing or cutting of the skin. If the electrode 520 were placed on theapex or tip of the microneedle, this mechanical stress may delaminatethe electrochemical sensing coating on the electrode surface when themicroneedle is inserted, and/or cause a small yet interfering amount oftissue to be transported onto the active sensing portion of theelectrode. Thus, placing the electrode 520 sufficiently offset from themicroneedle apex may improve sensing accuracy. For example, in somevariations, a distal edge of the electrode 520 may be located at leastabout 10 μm (e.g., between about 20 μm and about 30 μm) from the distalapex or tip of the microneedle, as measured along a longitudinal axis ofthe microneedle.

The body portion 512 of the microneedle 510 may further include anelectrically conductive pathway extending between the electrode 520 anda backside electrode or other electrical contact (e.g., arranged on abackside of the substrate of the microneedle array). The backsideelectrode may be soldered to a circuit board, enabling electricalcommunication with the electrode 520 via the conductive pathway. Forexample, during use, the in-vivo sensing current (inside the dermis)measured at a working electrode is interrogated by the backsideelectrical contact, and the electrical connection between the backsideelectrical contact and the working electrode is facilitated by theconductive pathway. In some variations, this conductive pathway may befacilitated by a metal via running through the interior of themicroneedle body portion (e.g., shaft) between the microneedle'sproximal and distal ends. Alternatively, in some variations theconductive pathway may be provided by the entire body portion beingformed of a conductive material (e.g., doped silicon). In some of thesevariations, the complete substrate on which the microneedle array 500 isbuilt upon may be electrically conductive, and each microneedle 510 inthe microneedle array 500 may be electrically isolated from adjacentmicroneedles 510 as described below. For example, in some variations,each microneedle 510 in the microneedle array 500 may be electricallyisolated from adjacent microneedles 510 with an insulative barrierincluding electrically insulative material (e.g., dielectric materialsuch as silicon dioxide) that surrounds the conductive pathway extendingbetween the electrode 520 and backside electrical contact. For example,body portion 512 may include an insulative material that forms a sheatharound the conductive pathway, thereby preventing electricalcommunication between the conductive pathway and the substrate. Otherexample variations of structures enabling electrical isolation amongmicroneedles are described in further detail below.

Such electrical isolation among microneedles in the microneedle arraypermits the sensors to be individually addressable. This individuallyaddressability advantageously enables independent and parallelizedmeasurement among the sensors, as well as dynamic reconfiguration ofsensor assignment (e.g., to different analytes). In some variations, theelectrodes in the microneedle array can be configured to provideredundant analyte measurements, which is an advantage over conventionalanalyte monitoring devices. For example, redundancy can improveperformance by improving accuracy (e.g., averaging multiple analytemeasurement values for the same analyte which reduces the effect ofextreme high or low sensor signals on the determination of analytelevels) and/or improving reliability of the device by reducing thelikelihood of total failure.

In some variations, as described in further detail below with respectivedifferent variations of the microneedle, the microneedle array may beformed at least in part with suitable semiconductor and/or MEMSfabrication techniques and/or mechanical cutting or dicing. Suchprocesses may, for example, be advantageous for enabling large-scale,cost-efficient manufacturing of microneedle arrays. For example, in somevariations, the microneedle array may be formed at least in part usingtechniques described in U.S. patent application Ser. No. 15/913,709,which is incorporated herein in its entirety by this reference.

Microneedle Structures

Described herein are multiple example variations of microneedlestructure incorporating one or more of the above-described microneedlefeatures for a microneedle array in an analyte monitoring device.

In some variations, a microneedle may have a generally columnar bodyportion and a tapered distal portion with an electrode. For example,FIGS. 7A-7C illustrate an example variation of a microneedle 700extending from a substrate 702. FIG. 7A is a side cross-sectional viewof a schematic of microneedle 700, while FIG. 7B is a perspective viewof the microneedle 700 and FIG. 7C is a detailed perspective view of adistal portion of the microneedle 700. As shown in FIGS. 7B and 7C, themicroneedle 700 may include a columnar body portion 712, a tapereddistal portion 714 terminating in an insulated distal apex 716, and anannular electrode 720 that includes a conductive material (e.g., Pt, Ir,Au, Ti, Cr, Ni, etc.) and is arranged on the tapered distal portion 714.As shown in FIG. 7A, the annular electrode 720 may be proximal to (oroffset or spaced apart from) the distal apex 716. For example, theelectrode 720 may be electrically isolated from the distal apex 716 by adistal insulating surface 715 a including an insulating material (e.g.,SiO₂). In some variations, the electrode 720 may also be electricallyisolated from the columnar body portion 712 by a second distalinsulating surface 715 b. The electrode 720 may be in electricalcommunication with a conductive core 740 (e.g., conductive pathway)passing along the body portion 712 to a backside electrical contact 730(e.g., made of Ni/Au alloy) or other electrical pad in or on thesubstrate 702. For example, the body portion 712 may include aconductive core material (e.g., highly doped silicon). As shown in FIG.7A, in some variations, an insulating moat 713 including an insulatingmaterial (e.g., SiO₂) may be arranged around (e.g., around theperimeter) of the body portion 712 and extend at least partially throughthe substrate 702. Accordingly, the insulating moat 713 may, forexample, help prevent electrical contact between the conductive core 740and the surrounding substrate 702. The insulating moat 713 may furtherextend over the surface of the body portion 712. Upper and/or lowersurfaces of the substrate 702 may also include a layer of substrateinsulation 704 (e.g., SiO₂). Accordingly, the insulation provided by theinsulating moat 713 and/or substrate insulation 704 may contribute atleast in part to the electrical isolation of the microneedle 700 thatenables individual addressability of the microneedle 700 within amicroneedle array. Furthermore, in some variations the insulating moat713 extending over the surface of the body portion 712 may function toincrease the mechanical strength of the microneedle 700 structure.

The microneedle 700 may be formed at least in part by suitable MEMSfabrication techniques such as plasma etching, also called dry etching.For example, in some variations, the insulating moat 713 around the bodyportion 712 of the microneedle may be made by first forming a trench ina silicon substrate by deep reactive ion etching (DRIE) from thebackside of the substrate, then filling that trench with a sandwichstructure of SiO₂/polycrystalline silicon (poly-Si)/SiO₂ by low pressurechemical vapor deposition (LPCVD) or other suitable process. In otherwords, the insulating moat 713 may passivate the surface of the bodyportion 712 of the microneedle, and continue as a buried feature in thesubstrate 702 near the proximal portion of the microneedle. By includinglargely compounds of silicon, the insulating moat 713 may provide goodfill and adhesion to the adjoining silicon walls (e.g., of theconductive core 740, substrate 702, etc.). The sandwich structure of theinsulating moat 713 may further help provide excellent matching ofcoefficient of thermal expansion (CTE) with the adjacent silicon,thereby advantageously reducing faults, cracks, and/or otherthermally-induced weaknesses in the insulating structure 713.

The tapered distal portion may be fashioned out by an isotropic dry etchfrom the frontside of the substrate, and the body portion 712 of themicroneedle 700 may be formed from DRIE. The frontside metal electrode720 may be deposited and patterned on the distal portion by specializedlithography (e.g., electron-beam evaporation) that permits metaldeposition in the desired annular region for the electrode 720 withoutcoating the distal apex 716. Furthermore, the backside electricalcontact 730 of Ni/Au may be deposited by suitable MEMS manufacturingtechniques (e.g., sputtering).

The microneedle 700 may have any suitable dimensions. By way ofillustration, the microneedle 700 may, in some variations, have a heightof between about 300 μm and about 500 μm. In some variations, thetapered distal portion 714 may have a tip angle between about 60 degreesand about 80 degrees, and an apex diameter of between about 1 μm andabout 15 μm. In some variations, the surface area of the annularelectrode 720 may include between about 9,000 μm² and about 11,000 μm²,or about 10,000 μm². FIG. 8 illustrates various dimensions of an examplevariation of a columnar microneedle with a tapered distal portion andannular electrode, similar to microneedle 700 described above.

FIG. 9 illustrates another example variation of a microneedle 900 havinga generally columnar body portion. The microneedle 900 may be similar tomicroneedle 700 as described above, except as described below. Forexample, like the microneedle 700, the microneedle 900 may include acolumnar body portion 912, and a tapered distal portion 914 terminatingin an insulated distal apex 916. The microneedle 900 may further includean annular electrode 920 that includes a conductive material and isarranged on the tapered distal portion 914 at a location proximal to (oroffset from or spaced apart from) the distal apex 916. Other elements ofmicroneedle 900 have numbering similar to corresponding elements ofmicroneedle 700.

However, compared to the microneedle 700, the microneedle 900 may have asharper tip at the distal apex 916 and a modified insulating moat 913.For example, the distal apex 916 may have a sharper tip angle, such asbetween about 25 degrees and about 45 degrees, and an apex radius ofless than about 100 nm, which provides a sharper microneedle profilethat may penetrate skin with greater ease, lower velocity, less energy,and/or less trauma. Furthermore, in contrast to the insulating moat 713(which extends through the substrate 702 and along the height of themicroneedle body portion 712 as shown in FIG. 7A), the modifiedinsulating moat 913 may extend only through the substrate 902 such thatthe sandwich structure filling the trench (e.g., created by DRIE asdescribed above) forms only the buried feature in the substrate.Although the sidewall of the microneedle 900 is shown in FIG. 9 asextending generally orthogonal to the substrate surface, it should beunderstood that because the modified insulating moat 913 need not extendthe entire height of the microneedle body portion 712, in somevariations the sidewall of the microneedle 900 may be angled atnon-orthogonal angles relative to the substrate (e.g., the sidewall mayhave a slight positive taper of between about 1 degree to about 10degrees, or between about 5 degrees and about 10 degrees).

In some variations, the rest of the microneedle surface 900 (aside fromthe annular electrode 920) may include an insulating material extendingfrom substrate insulation 904. For example, a layer of an insulatingmaterial (e.g., SiO₂) may extend from a frontside surface of thesubstrate 902 to provide a body portion insulation 918, and may furtherextend up over a proximal edge of the electrode 920 as shown in FIG. 9 .Another region of insulating material may similarly cover a distal edgeof the electrode 920 and insulate the distal apex 916. Such region ofinsulating material and/or modified insulating moat 913 may help preventelectrical contact between the conductive core 940 and the surroundingsubstrate 902. Accordingly, like the microneedle 700, the microneedle900 may maintain electrical isolation for individual addressabilitywithin a microneedle array. In some variations, the process to formmicroneedle 900 may result in higher yield and/or provide lowerproduction cost compared to the process to form microneedle 700.

The microneedle 900 may have any suitable dimensions. By way ofillustration, the microneedle 900 may, in some variations, include aheight of between about 400 μm and about 600 μm, or about 500 μm. Insome variations, the tapered distal portion 914 may have a tip angle ofbetween about 25 degrees and about 45 degrees, with a tip radius of lessthan about 100 nm. Furthermore, the microneedle may have a shaftdiameter of between about 160 μm and about 200 μm. FIG. 10 illustratesadditional various dimensions of an example variation of a columnarmicroneedle with a tapered distal portion and annular electrode, similarto microneedle 900 described above.

FIGS. 27A-27F illustrate another example variation of a microneedle 2700having a generally columnar body portion. The microneedle 2700 may besimilar to microneedle 700 as described above, except as describedbelow. For example, as shown in FIG. 27B, like the microneedle 700, themicroneedle 2700 may include a columnar body portion 2712, and a tapereddistal portion arranged on a cylinder 2713 and terminating in aninsulated distal apex 2716. The cylinder 2613 may be insulated and havea smaller diameter than the columnar body portion 2712. The microneedle2700 may further include an annular electrode 2720 that includes aconductive material and is arranged on the tapered distal portion at alocation proximal to (or offset or spaced apart from) the distal apex2916. Other elements of microneedle 2700 as shown in FIGS. 27A-27F havenumbering similar to corresponding elements of microneedle 700.

However, the electrode 2720 on the microneedle 2700 may include a tipcontact trench 2722. This contact trench may be configured to helpestablish ohmic contact between the electrode 2720 and the underlyingconductive core 2740 of the microneedle. In some variations, the shapeof the tip contact trench 2722 may include an annular recess formed inthe surface of the conductive core 2740 (e.g., into the body portion ofthe microneedle, or otherwise in contact with a conductive pathway inthe body portion) such that when the electrode 2720 material isdeposited onto the conductive core 2740, the electrode 2720 with the tipcontact trench 2722 may have a stepped profile when viewed from theside. The tip contact trench 2722 may advantageously help provide amargin of error to ensure contact between the electrode 2720 and theunderlying conductive core 2740. Any of the other microneedle variationsdescribed herein may also have a similar tip contact trench to helpensure contact between the electrode (which may be, for example, aworking electrode, reference electrode, counter electrode, etc.) with aconductive pathway within the microneedle.

FIGS. 28A and 28B illustrate additional various dimensions of an examplevariation of a columnar microneedle with a tapered distal portion andannular electrode, similar to microneedle 2700 described above. Forexample, the variation of the microneedle shown in FIGS. 28A and 28B mayhave a tapered distal portion generally having a taper angle of about 80degrees (or between about 78 degrees and about 82 degrees, or betweenabout 75 degrees and about 85 degrees), and a cone diameter of about 140μm (or between about 133 μm and about 147 μm, or between about 130 μmand about 150 μm). The cone of the tapered distal portion may bearranged on a cylinder such that the overall combined height of the coneand cylinder is about 110 μm (or between about 99 μm and about 116 μm,or between about 95 μm and about 120 μm). The annular electrode on thetapered distal portion may have an outer or base diameter of about 106μm (or between about 95 μm and about 117 μm, or between about 90 μm andabout 120 μm), and an inner diameter of about 33.2 μm (or between about30 μm and about 36 μm, or between about 25 μm and about 40 μm). Thelength of the annular electrode, as measured along the slope of thetapered distal portion, may be about 57 μm (or between about 55 μm andabout 65 μm), and the overall surface area of the electrode may be about12,700 μm² (or between about 12,500 μm² and about 12,900 μm², or betweenabout 12,000 μm² and about 13,000 μm²). As shown in FIG. 28B, theelectrode may furthermore have a tip contact trench extending around acentral region of the cone of the tapered distal portion, where thecontact trench may have a width of about 11 μm (or between about 5 μmand about 50 μm, between about 10 μm and about 12 μm, or between about 8μm and about 14 μm) as measured along the slope of the tapered distalportion, and a trench depth of about 1.5 μm (or between about 0.1 μm andabout 5 μm, or between about 0.5 μm and about 1.5 μm, or between about1.4 μm and about 1.6 μm, or between about 1 μm and about 2 μm). Themicroneedle has an insulated distal apex having a diameter of about 5.5μm (or between about 5.3 μm and about 5.8 μm, or between about 5 μm andabout 6 μm).

In some variations, a microneedle may have a generally pyramidal bodyportion and a tapered distal portion with an electrode. For example,FIG. 11A illustrates an example variation of a microneedle 1100 having agenerally pyramidal body portion 1112 and a tapered distal portion 1114extending from the body portion 1112. The microneedle 1100 may alsoinclude an annular electrode 1120 arranged on the tapered distal portion1114 and proximal to an insulated distal apex 1116. The electrode 1120may be conductively coupled via a conductive pathway through theconductive core 1140 of the microneedle to a backside electrical contact1130. Like the microneedle 900 described above with respect to FIG. 9 ,the microneedle 1100 may include an insulating moat 1113 that isarranged around the base of the body portion 1112 and extends throughthe substrate 1102 to provide electrical insulation around themicroneedle 1100 (e.g., for individual addressability) and help preventelectrical contact between the conductive core 1140 and the surroundingsubstrate 1102. However, in contrast to the insulating moat 913 shown inFIG. 9 , the insulating moat 1113 may be offset from the base of themicroneedle 1100. The moat may, for example, be offset between about 10μm and about 400 μm, between about 10 μm and about 300 μm, between about10 μm and about 200 μm, or between about 10 μm and about 100 μm fromwhere the base of the microneedle 1100 meets the substrate 1102 to whichit is attached. In some variations, the insulating moat may include afiller material including parylene, Si₃N₄, and SiO₂, which may providefor low thermal stress and an insulating material that is chemical- andwater-resistant. Additional body portion insulation 1118 may extend froma frontside surface of the substrate 1102 up to the proximal edge of theelectrode 1120. Another region of insulating material may extend fromthe distal edge of the electrode 1120 and insulate the distal apex 1116.

As shown in FIG. 11B, in some variations a microneedle 1100 having apyramidal body portion 1112 may include a polygonal base, though thebase may have any suitable shape (e.g., circular). The pyramidal bodyportion 1112 may include a plurality of planar facets each extendingfrom a respective of the polygonal base of the microneedle. In somevariations, the planar facets may include anisotropically etched <311>planar facets for increased mechanical strength (e.g., compressivestrength and shear strength) of the microneedle 1110 and/or increasedelectrode surface area relative to a circular cone with a non-planarfaceted surface. For example, the microneedle 1110 may have an octagonalbase with anisotropically etched <311> planar facets that increase themechanical strength and increase the metallization surface of themicroneedle 110 for the electrode surface.

The microneedle 1100 may be formed at least in part by suitable MEMSfabrication techniques. For example, the microneedle pyramidal structuremay be formed by a timed anisotropic wet etch of a silicon wafersubstrate. To form the annular electrode surface, metal deposition onthe tapered distal portion of the microneedle may be performed, such asusing specialized lithographic techniques as described above withrespect to electrode 720, without coating the distal apex 1116. However,compared to the process described above to form microneedle 700, much ofthe process to form microneedle 1100 does not involve expensive RIEtechniques, which may thereby substantially reduce manufacturing costs.Furthermore, in some variations, instead of utilizing dry etch processesas described above with respect to microneedle 700, a process of formingthe microneedle 1100 may include mechanical dicing, bulk micromachining,or other cutting techniques to shape the microneedle 1100 into having apyramidal body. Furthermore, such techniques may be performed at a largescale, so as to form, for example, multiple microneedles 1110 arrangedin an array as shown in FIG. 11C.

The microneedle 1100 may have any suitable dimensions. By way ofillustration, the microneedle 1100 may, in some variations, have aheight of between about 400 μm and about 600 μm, or about 500 μm. Insome variations, the tapered distal portion 714 may have a tip anglebetween about 30 degrees and about 50 degrees, or about 40 degrees,which may provide a good balance between sharpness for skin penetrationand lithography processability on the sloped surface on which theelectrode 1120 is to be disposed.

FIG. 12 illustrates various dimensions of an example variation of apyramidal microneedle with a tapered distal portion having planar facetsand an electrode arranged on at least a portion of the planar facets.While in some variations the electrode may be annular or annular-like inthat all of the planar facets on the pyramidal microneedle may include ametallization surface for the electrode, it should be understood thatalternatively, in some variations only a portion of the planar facets onthe pyramidal microneedle may include a metallization surface (e.g.,one, two, three, four, five, six, or seven planar facets of a pyramidalmicroneedle having an octagonal base and eight planar facets extendingdistally from the octagonal base).

In some variations, a pyramidal microneedle may be similar to thatdescribed above with respect to FIG. 11A, except that the microneedlemay have an asymmetrical shape as shown in FIGS. 13A and 13B. Forexample, in some variations as shown in FIG. 13A, a microneedle 1300 mayhave a non-circular or polygonal (e.g., square, octagonal) base, but maytaper in a radially asymmetric manner. For example, the microneedle 1300may include at least one cut surface 1350 (e.g., planar surface) that isoffset from the distal apex 1316 of the microneedle (that is, notextending through a central z-axis defined as passing from the base ofthe microneedle 1300 to the distal apex 1316. The insulated distal apex1316 may be kept intact so as to not compromise surface area formetallization for the electrode. In some variations, the cut surface1350 may be angled at a non-orthogonal angle relative to the base of themicroneedle (and/or surface of the substrate 1302), as shown in FIG.13A. For example, in some variations the cut surface may configured toproduce a sharpened asymmetrical distal tip at distal apex 1316 that isless than about 50 degrees, less than 40 degrees, less than about 30degrees, or less than about 20 degrees. Alternatively, in somevariations the cut surface 1350 may be angled normal to or orthogonal tothe base of the microneedle (and/or surface of the substrate 1302).

Additionally or alternatively, as shown in FIG. 13A, an examplevariation of an asymmetric microneedle 1300 may have a polygonal (e.g.,octagonal) base, but include various sloped surfaces that taper atdifferent angles. As shown in FIG. 13A, a body portion 1316 of themicroneedle 1300 may have a first taper angle (A) and a second taperangle (B) measured relative to a base of the body portion (and/orsurface of the substrate 1302). The second taper angle (B) may begreater than the first taper angle (A) such that the microneedle has asharper penetrating tip extending from a stable, mechanically strongbase. For example, in some variations, the first taper angle (A) may bebetween about 10 degrees and about 30 degrees, between about 15 degreesand about 25 degrees, or about 20 degrees. Additionally, in somevariations, the second taper angle (B) may be between about 60 degreesand about 80 degrees, between about 65 degrees and about 75 degrees, orabout 70 degrees.

FIGS. 13C-13E depict a series of steps in an example variation offorming a pyramidal microneedle with an asymmetric cut surface. As shownin FIG. 13C, a symmetric pyramidal microneedle with two taper angles maybe formed through an anisotropic wet etch process. The two taper anglesof the microneedle may include, for example, a first taper angle ofabout 20 degrees located near the base of the microneedle, and a secondtaper angle of about 70 degrees located distal to the first tape angle,thereby forming progressively sloping surfaces (e.g., along planarfacets of the pyramidal microneedle). As shown in FIG. 13D, a dicingblade may be applied at an angle offset from the distal apex of themicroneedle, so as to form a cut surface similar to cut surface 1350described above. The cut surface may leave a reduced microneedle basediameter (e.g., between about 150 μm and about 190 μm, or about 170 μm)so as to result in low tissue trauma. As shown in FIG. 13E, theresulting microneedle (with its offset cut surface) is asymmetric buthas an intact, sharp distal apex.

Like the pyramidal microneedle 1100 described above with respect to FIG.11A, the microneedle 1300 may derive its mechanical strength at least inpart from anisotropically etched <311> planes and the pyramidal shape.However, an asymmetric pyramidal microneedle with a asymmetric cutsurface may be advantageous in that it may reduce the longitudinal shearforces compared to a symmetric microneedle having similar dimensions butlacking the asymmetric cut. Furthermore, a sharper (e.g., more acuteangle) distal microneedle tip may be achieved with such an asymmetriccut surface. Although the cut surface 1350 is shown in FIG. 13A aspositioned at a non-orthogonal angle relative to the base of themicroneedle, alternatively as described above, in some variations thecut surface 1350 may be generally orthogonal or normal to the base ofthe microneedle (and/or surface of the substrate 1302), which mayfurther reduce the longitudinal shear forces in the microneedle.

In some variations, a microneedle may be similar to those describedabove, except that the microneedle may include a columnar body portionand a pyramidal distal portion. For example, as shown in FIG. 14A, acolumnar-pyramidal microneedle 1400 may include a columnar body portion1412 that may extend from a polygonal (e.g., octagonal) base out of anon-electrically conductive substrate 1402 such as intrinsic (undoped)silicon. Additionally, the columnar-pyramidal microneedle 1400 mayinclude a tapered distal portion 1414 having a pyramidal shape with aplurality of planar facets. For example, the columnar-pyramidalmicroneedle 1400 may include a tapered distal portion 1414 having apyramidal shape with eight facets extending from the octagonal columnarbody portion 1412. However, the pyramidal shape may have any suitablenumber of planar facets (e.g., one, two, three, four, five, six, seven,nine, or more). An annular electrode 1420 may be formed on all theplanar facets of the pyramidal distal portion 1414, or on only a portionof the planar facets (e.g., on one, two, three, four, five, six, sevenfacets) may include a metallization surface for the electrode. Similarto that described above, the columnar body portion 1412 may include aconductive core including an electrically conductive materialfunctioning as a conductive pathway for signals to and from theelectrode 142. The columnar body portion 1412 may further include aninsulation material 1418 may extend along the body portion 1412 and upto (or slightly overlapping) a proximal edge of the electrode 1420. Thedistal apex 1416 may or may not be covered by similar insulationmaterial.

In some variations, the tapered distal portion 1414 may be similar tothat described above with respect to FIGS. 11A-11C, 12 , and/or 13A-13E.For example, the tapered distal portion 1414 may be formed usinganisotropic wet etching techniques. The electrode 1420 may be formed onthe tapered distal portion 1414 by lithography, electrodeposition orother suitable technique. The tapered distal portion 1414 may then beprotected by an etch resistant material while the body portion 1412 isformed out of the substrate by dry etching (e.g., DRIE) or othersuitable process(es).

The combination of columnar and pyramidal aspects of the microneedle1400 has a number of advantages. Similar to that described above, thetapered distal portion 1414 and apex 1416 have high mechanical strengthdue to the <311> wet etched planes and the pyramidal shape.Additionally, because the substrate is formed from a non-conductivematerial, an insulation “moat” as described above may not be required toelectrically isolate the microneedle, thereby simplifying and reducingcost of fabrication. The absence of the insulation moat also permitsmaterial continuity in the substrate, which may lead to bettermechanical integrity of the overall microneedle array structure.

Although the columnar-pyramidal microneedle 1400 is described above asincluding a non-conductive substrate, it should be understoodalternatively, in some variations a columnar-pyramidal microneedle mayinclude a conductive core extending from a conductive substrate (e.g.,doped silicon). For example, in some variations the columnar bodyportion 1412 may be similar to that described above with respect toFIGS. 7A-7C, and 8-10 (e.g., may include an insulation moat toelectrically isolate the microneedle, etc.).

In some variations of microneedle arrays including one or moremicroneedles 1400, conductive pathways may be formed in thenon-conductive substrate to facilitate communication with theelectrode(s) 1420. For example, as described above, the body portion1412 of each microneedle may include a conductive core including aconductive material. Such conductive material may extend between theelectrode 1420 to the substrate 1402. As shown in FIG. 15D, themicroneedle array may include one or more connectors 1510 made of aconductive material (e.g., gold, aluminum) that is each in turn coupledto a backside electrical contact 1530 for further sensor communication.In some variations, as shown FIGS. 15A-15D, the one or more connectors1510 may extend laterally along the surface of the substrate and thenconnect to the backside electrical contact 1530 with a conductive via1520 within the substrate.

Additional details of example variations of microneedle arrayconfigurations are described in further detail below.

Electrodes

As described above, each microneedle in the microneedle array mayinclude an electrode. In some variations, multiple distinct types ofelectrodes may be included among the microneedles in the microneedlearray. For example, in some variations the microneedle array mayfunction as an electrochemical cell operable in an electrolytic mannerwith three types of electrodes. In other words, the microneedle arraymay include at least one working electrode, at least one counterelectrode, and at least one reference electrode. Thus, the microneedlearray may include three distinct electrode types, though one or more ofeach electrode type may form a complete system (e.g., the system mightinclude multiple distinct working electrodes). Furthermore, multipledistinct microneedles may be electrically joined to form an effectiveelectrode type (e.g., a single working electrode may be formed from twoor more connected microneedles with working electrode sites). Each ofthese electrode types may include a metallization layer and may includeone or more coatings or layers over the metallization layer that helpfacilitate the function of that electrode.

Generally, the working electrode is the electrode at which oxidationand/or reduction reaction of interest occurs for detection of an analyteof interest. The counter electrode functions to source (provide) or sink(accumulate) the electrons, via an electrical current, that are requiredto sustain the electrochemical reaction at the working electrode. Thereference electrode functions to provide a reference potential for thesystem; that is, the electrical potential at which the working electrodeis biased is referenced to the reference electrode. A fixed,time-varying, or at least controlled potential relationship isestablished between the working and reference electrodes, and withinpractical limits no current is sourced from or sinked to the referenceelectrode. Additionally, to implement such a three-electrode system, theanalyte monitoring device may include a suitable potentiostat orelectrochemical analog front end to maintain a fixed potentialrelationship between the working electrode and reference electrodecontingents within the electrochemical system (via an electronicfeedback mechanism), while permitting the counter electrode todynamically swing to potentials required to sustain the redox reactionof interest.

Working Electrode

As described above, the working electrode is the electrode at which theoxidation and/or reduction reaction of interest occurs. In somevariations, sensing may be performed at the interface of the workingelectrode and interstitial fluid located within the body (e.g., on anouter surface of the overall microneedle). In some variations, a workingelectrode may include an electrode material and a biorecognition layerin which a biorecognition element (e.g., enzyme) is immobilized on theworking electrode to facilitate selective analyte quantification. Insome variations, the biorecognition layer may also function as aninterference-blocking layer and may help prevent endogenous and/orexogenous species from directly oxidizing (or reducing) at theelectrode.

A redox current detected at the working electrode may be correlated to adetected concentration of an analyte of interest. This is becauseassuming a steady-state, diffusion-limited system, the redox currentdetected at the working electrode follows the Cottrell relation below:

${i(t)} = \frac{{nFA}\sqrt{D}C}{\sqrt{\pi t}}$where n is the stoichiometric number of electrons mitigating a redoxreaction, F is Faraday's constant, A is electrode surface area, D is thediffusion coefficient of the analyte of interest, C is the concentrationof the analyte of interest, and t is the duration of time that thesystem is biased with an electrical potential. Thus, the detectedcurrent at the working electrode scales linearly with the analyteconcentration.

Moreover, because the detected current is a direct function of electrodesurface area A, the surface area of the electrode may be increased toenhance the sensitivity (e.g., amperes per molar of analyte) of thesensor. For example, multiple singular working electrodes may be groupedinto arrays of two or more constituents to increase total effectivesensing surface area. Additionally or alternatively, to obtainredundancy, multiple working electrodes may be operated as parallelizedsensors to obtain a plurality of independent measures of theconcentration of an analyte of interest. The working electrode caneither be operated as the anode (such that an analyte is oxidized at itssurface), or as the cathode (such that an analyte is reduced at itssurface).

FIG. 16A depicts a schematic of an exemplary set of layers for a workingelectrode 1610. For example, as described above, in some variations theworking electrode 1610 may include an electrode material 1612 and abiorecognition layer including a biorecognition element. The electrodematerial 1612 functions to encourage the electrocatalytic detection ofan analyte or the product of the reaction of the analyte and thebiorecognition element. The electrode material 1612 also provides ohmiccontact and routes an electrical signal from the electrocatalyticreaction to processing circuitry. In some variations, the electrodematerial 1612 may include platinum as shown in FIG. 16A. However, theelectrode material 1612 may alternatively include, for example,palladium, iridium, rhodium, gold, ruthenium, titanium, nickel, carbon,doped diamond, or other suitable catalytic and inert material.

In some variations, the electrode material 1612 may be coated with ahighly porous electrocatalytic layer, such as a platinum black layer1613, which may augment the electrode surface area for enhancedsensitivity. Additionally or alternatively, the platinum black layer1613 may enable the electrocatalytic oxidation or reduction of theproduct of the biorecognition reaction facilitated by the biorecognitionlayer 1614. However, in some variations the platinum black layer 1613may be omitted (as shown in FIGS. 16D and 16G, for example). Theelectrode may enable the electrocatalytic oxidation or reduction of theproduct of the biorecognition reaction if the platinum black layer 1613is not present.

The biorecognition layer 1614 may be arranged over the electrodematerial 1612 (or platinum black layer 1613 if it is present) andfunctions to immobilize and stabilize the biorecognition element whichfacilitates selective analyte quantification for extended time periods.In some variations, the biorecognition element may include an enzyme,such as an oxidase. As an exemplary variation for use in a glucosemonitoring system, the biorecognition element may include glucoseoxidase, which converts glucose, in the presence of oxygen, to anelectroactive product (i.e., hydrogen peroxide) that can be detected atthe electrode surface. Specifically, the redox equation associated withthis exemplary variation is Glucose+Oxygen→HydrogenPeroxide+Gluconolactone (mediated by glucose oxidase); HydrogenPeroxide→Water+Oxygen (mediated by applying an oxidizing potential atthe working electrode).

However, in other variations the biorecognition element may additionallyor alternatively comprise another suitable oxidase or oxidoreductaseenzyme such as lactate oxidase, alcohol oxidase, beta-hydroxybutyratedehydrogenase, tyrosinase, catalase, ascorbate oxidase, cholesteroloxidase, choline oxidase, pyruvate oxidase, urate oxidase, urease,and/or xanthine oxidase.

In some variations, the biorecognition element may be cross-linked withan amine-condensing carbonyl chemical species that may help stabilizethe biorecognition element within the biorecognition layer 1614. Asfurther described below, in some variations, the cross-linking of thebiorecognition element may result in the microneedle array beingcompatible with ethylene oxide (EO) sterilization, which permitsexposure of the entire analyte monitoring device (including sensingelements and electronics) to the same sterilization cycle, therebysimplifying the sterilization process and lowering manufacture costs.For example, the biorecognition element may be cross-linked withglutaraldehyde, formaldehyde, glyoxal, malonaldehyde, succinaldehyde,and/or other suitable species. In some variations, the biorecognitionelement may be cross-linked with such an amine-condensing carbonylchemical species to form cross-linked biorecognition element aggregates.Cross-linked biorecognition element aggregates that have at least athreshold molecular weight may then be embedded in a conducting polymer.By embedding only those aggregates that have a threshold molecularweight, any uncross-linked enzymes may be screened out and notincorporated into the biorecogntion layer. Accordingly, only aggregateshaving a desired molecular weight may be selected for use in theconducting polymer, to help ensure that only sufficiently stabilized,cross-linked enzyme entities are included in the biorecognition layer,thereby contributing to a biorecognition layer that is overall bettersuited for EO sterilization without loss in sensing performance. In somevariations, only cross-linked aggregates that have a molecular weightthat is at least twice that of glucose oxidase may be embedded in theconducting polymer.

In some variations, the conducting polymer may be permselective tocontribute to the biorecognition layer's robustness against circulatingandrogynous electroactive species (e.g., ascorbic acid, vitamin C,etc.), fluctuations of which may adversely affect the sensitivity of thesensor. Such a permselective conducting polymer in the biorecognitionlayer may further be more robust against pharmacological interferences(e.g., acetaminophen) in the interstitial fluid that may affect sensoraccuracy. Conducting polymers may be made permselective by, for example,removing excess charge carriers by an oxidative electropolymerizationprocess or by neutralizing these charge carriers with a counter-iondopant, thereby transforming the conducting polymer into anon-conducting form. These oxidatively-polymerized conducting polymersexhibit permselectivity and are hence able to reject ions of similarcharge polarity to the dopant ion (net positive or negative) or by viasize exclusion due to the dense and compact form of the conductingpolymers.

Furthermore, in some variations the conducting polymer may exhibitself-sealing and/or self-healing properties. For example, the conductingpolymer may undergo oxidative electropolymerization, during which theconducting polymer may lose its conductivity as the thickness of thedeposited conducting polymer on the electrode increases, until the lackof sufficient conductivity causes the deposition of additionalconducting polymer to diminish. In the event that the conducting polymerhas succumbed to minor physical damage (e.g., during use), the polymericbackbone may re-assemble to neutralize free charge and thereby loweroverall surface energy of the molecular structure, which may manifest asself-sealing and/or self-healing properties.

In some variations, the working electrode may further include adiffusion-limiting layer 1615 arranged over the biorecognition layer1614. The diffusion-limiting layer 1615 may function to limit the fluxof the analyte of interest in order to reduce the sensitivity of thesensor to endogenous oxygen fluctuations. For example, thediffusion-limiting layer 1615 may attenuate the concentration of theanalyte of interest so that it becomes the limiting reactant to anaerobic enzyme. However, in some variation (e.g., if the biorecognitionelement is not aerobic), the diffusion-limiting layer 1615 may beomitted.

The working electrode may further include, in some variations, ahydrophilic layer 1616 that provides for a biocompatible interface to,for example, reduce the foreign body response. However, in somevariations the hydrophilic layer 1616 may be omitted (e.g., if thediffusion-limiting layer expresses hydrophilic moieties to serve thispurpose), as shown in FIGS. 16D and 16G, for example.

Counter Electrode

As described above, the counter electrode is the electrode that issourcing or sinking electrons (via an electrical current) required tosustain the electrochemical reaction at the working electrode. Thenumber of counter electrode constituents can be augmented in the form ofa counter electrode array to enhance surface area such that thecurrent-carrying capacity of the counter electrode does not limit theredox reaction of the working electrode. It thus may be desirable tohave an excess of counter electrode area versus the working electrodearea to circumvent the current-carrying capacity limitation. If theworking electrode is operated as an anode, the counter electrode willserve as the cathode and vice versa. Similarly, if an oxidation reactionoccurs at the working electrode, a reduction reaction occurs at thecounter electrode and vice versa. Unlike the working or referenceelectrodes, the counter electrode is permitted to dynamically swing toelectrical potentials required to sustain the redox reaction of intereston the working electrode.

As shown in FIG. 16B, a counter electrode 1620 may include an electrodematerial 1622, similar to electrode material 1612. For example, like theelectrode material 1612, the electrode material 1622 in the counterelectrode 1620 may include a noble metal such as gold, platinum,palladium, iridium, carbon, doped diamond, and/or other suitablecatalytic and inert material.

In some variations, the counter electrode 1620 may have few or noadditional layers over the electrode material 1632. However, in somevariations the counter electrode 1620 may benefit from increase surfacearea to increase the amount of current it can support. For example, thecounter electrode material 1632 may be textured or otherwise roughenedin such a way to augment the surface area of the electrode material 1632for enhanced current sourcing or sinking ability. Additionally oralternatively, the counter electrode 1620 may include a layer ofplatinum black 1624, which may augment electrode surface as describedabove with respect to some variations of the working electrode. However,in some variations of the counter electrode, the layer of platinum blackmay be omitted (e.g., as shown in FIG. 16E). In some variations, thecounter electrode may further include, a hydrophilic layer that providesfor a biocompatible interface to, for example, reduce the foreign bodyresponse.

Additionally or alternatively, in some variations as shown in FIG. 16H,the counter electrode 1620 may include a diffusion-limiting layer 1625(e.g., arranged over the electrode). The diffusion-limiting layer 1625may, for example, be similar to the diffusion-limiting layer 1615described above with respect to FIG. 16A.

Reference Electrode

As described above, the reference electrode functions to provide areference potential for the system; that is, the electrical potential atwhich the working electrode is biased is referenced to the referenceelectrode. A fixed or at least controlled potential relationship may beestablished between the working and reference electrodes, and withinpractical limits no current is sourced from or sinked to the referenceelectrode.

As shown in FIG. 16C, a reference electrode 1630 may include anelectrode material 1632, similar to electrode material 1612. In somevariations, like the electrode material 1612, the electrode material1632 in the reference electrode 1630 may include a metal salt or metaloxide, which serves as a stable redox coupled with a well-knownelectrode potential. For example, the metal salt may, for example,include silver-silver chloride (Ag/AgCl) and the metal oxide may includeiridium oxide (IrOx/Ir₂O₃/IrO₂). In other variations, noble and inertmetal surfaces may function as quasi-reference electrodes and includegold, platinum, palladium, iridium, carbon, doped diamond, and/or othersuitable catalytic and inert material. Furthermore, in some variationsthe reference electrode 1630 may be textured or otherwise roughened insuch a way to enhance adhesion with any subsequent layers. Suchsubsequent layers on the electrode material 1632 may include a platinumblack layer 1634. However, in some variations, the platinum black layermay be omitted (e.g., as shown in FIGS. 16F and 16I).

The reference electrode 1630 may, in some variations, further include aredox-couple layer 1636, which main contain a surface-immobilized,solid-state redox couple with a stable thermodynamic potential. Forexample, the reference electrode may operate at a stable standardthermodynamic potential with respect to a standard hydrogen electrode(SHE). The high stability of the electrode potential may be attained byemploying a redox system with constant (e.g., buffered or saturated)concentrations of each participant of the redox reaction. For example,the reference electrode may include saturated Ag/AgCl (E=+0.197V vs.SHE) or IrOx (E=+0.177 vs. SHE, pH=7.00) in the redox-couple layer 1636.Other examples of redox-couple layers 1636 may include a suitableconducting polymer with a dopant molecule such as that described in U.S.Patent Pub. No. 2019/0309433, which is incorporated in its entiretyherein by this reference. In some variations, the reference electrodemay be used as a half-cell to construct a complete electrochemical cell.

Additionally or alternatively, in some variations as shown in FIG. 16I,the reference electrode 1630 may include a diffusion-limiting layer 1635(e.g., arranged over the electrode and/or the redox-couple layer). Thediffusion-limiting layer 1635 may, for example, be similar to thediffusion-limiting layer 1615 described above with respect to FIG. 16A.

Exemplary Electrode Layer Formation

Various layers of the working electrode, counter electrode, andreference electrode may be applied to the microneedle array and/orfunctionalized, etc. using suitable processes such as those describedbelow.

In a pre-processing step for the microneedle array, the microneedlearray may be plasma cleaned in an inert gas (e.g., RF-generated inertgas such as argon) plasma environment to render the surface of thematerial, including the electrode material (e.g., electrode material1612, 1622, and 1632 as described above), to be more hydrophilic andchemically reactive. This pre-processing functions to not onlyphysically remove organic debris and contaminants, but also to clean andprepare the electrode surface to enhance adhesion of subsequentlydeposited films on its surface.

Working Electrode

Anodization: To configure the working electrode after the pre-processingstep, the electrode material 1612 may undergo an anodization treatmentusing an amperometry approach in which the electrode constituent(s)assigned for the working electrode function is (are) subject to a fixedhigh anodic potential (e.g., between +1.0-+1.3 V vs. Ag/AgCl referenceelectrode) for a suitable amount of time (e.g., between about 30 sec andabout 10 min) in a moderate-strength acid solution (e.g., 0.1-3M H₂SO₄).In this process, a thin, yet stable native oxide layer may be generatedon the electrode surface. Owing to the low pH arising at the electrodesurface, any trace contaminants may be removed as well.

In an alternative embodiment using a coulometry approach, anodizationcan proceed until a specified amount of charge has passed (measured inCoulombs). The anodic potential may be applied as described above;however, the duration of this might vary until the specified amount ofcharge has passed.

Activation: Following the anodization process, the working electrodeconstituents may be subjected to a cyclically-scanned potential waveformin an activation process using cyclic voltammetry. In the activationprocess, which may occur in a moderate-strength acid solution (e.g.0.1-3M H₂SO₄), the potential applied may time-varying in a suitablefunction (e.g., sawtooth function). For example, the voltage may belinearly scanned between a cathodic value (e.g., between −0.3-−0.2 V vs.Ag/AgCl reference electrode) and an anodic value (e.g., between+1.0-+1.3 V vs. Ag/AgCl reference electrode) in an alternating function(e.g., 15-50 linear sweep segments). The scan rate of this waveform cantake on a value between 1-1000 mV/sec. It should be noted that a currentpeak arising during the anodic sweep (sweep to positive extreme)corresponds to the oxidation of a chemical species, while the currentpeak arising during the ensuing cathodic sweep (sweep to negativeextreme) corresponds to the reduction of said chemical species.

Functionalization of the biorecognition layer: Following the activationprocess, the working electrode constituents may be functionalized withthe biorecognition layer 1614 such as that described above. Assumingthat the working electrode contingent of the microneedle array hasundergone the aforementioned steps, the potential applied may betime-varying in a sawtooth function. For example, a voltage may belinearly scanned between a cathodic value (e.g., between 0.0 V vs.Ag/AgCl reference electrode) and an anodic value (e.g., between +1.0 Vvs Ag/AgCl reference electrode) in an alternating function (e.g., 10linear sweep segments). In an example variation, the scan rate of thiswaveform can take on a value between about 1 mV/sec and about 10 mV/secin an aqueous solution comprised of a monomeric precursor to theentrapment conducting polymer and a cross-linked biorecognition element(e.g., enzyme, such as glucose oxidase). In this process, a thin film(e.g., between about 10 nm and about 1000 nm) of biorecognition layercomprising of polymer with a dispersed cross-linked biorecognitionelement may be generated (e.g., electrodeposited or electropolymerized)on the working electrode surface. In some variations, the conductingpolymer may include one or more of aniline, pyrrole, acetylene,phenylene, phenylene vinylene, phenylene diamine, thiophene,3,4-ethylenedioxythiophene, and aminophenylboronic acid. Thebiorecognition layer imparts a selective sensing capability towards ananalyte of interest, as described above.

In some variations, the working electrode surface may beelectrochemically roughened in order to enhance adhesion of thebiorecognition layer to the electrode material 1612 surface (and/or Ptblack layer). The roughening process may involve a cathodizationtreatment (e.g., cathodic deposition, a subset of amperometry) whereinthe electrode is subject to a fixed cathodic potential (e.g., between−0.4-+0.2 V vs. Ag/AgCl reference electrode) for a certain amount oftime (e.g., 5 sec-10 min) in an acid solution containing the desiredmetal cation dissolved therein (e.g., 0.01-100 mM H₂PtCl₆).Alternatively, the electrode is subject to a fixed cathodic potential(e.g., between about −0.4 to about +0.2 V vs. Ag/AgCl referenceelectrode) until a certain amount of charge has passed (e.g., 0.1 mC-100mC) in an acid solution containing the desired metal cation dissolvedtherein (e.g., 0.01-100 mM H₂PtCl₆). In this process, a thin, yet highlyporous layer of the metal may be generated on the electrode surface,thereby augmenting the electrode surface area dramatically. Additionallyor alternatively, in some variations as described above, elementalplatinum metal may deposited on the electrode to form or deposit aplatinum black layer 1613.

Functionalization of the diffusion-limiting layer: Following thefunctionalization of the biorecognition layer, the working electrodeconstituents may, in some variations, be functionalized with thediffusion-limiting layer. Assuming that the working electrode contingentof the microneedle array has undergone the aforementioned steps, one ormore of the following methods may be employed to apply thediffusion-limiting layer, which may be a thin film of thickness betweenabout 100 nm to about 10,000 nm.

In some variations, a diffusion-limiting layer may applied by a spraycoating method in which an aerosolized polymer formulation (dispersed inwater or a solvent) is applied to the microneedle array device with aspecified spray pattern and duration in a controlled-environmentsetting. This creates a thin film with the desired thickness andporosity required to restrict the diffusion of an analyte of interest tothe biorecognition layer.

In some variations, a diffusion-limiting layer may be applied by aplasma-induced polymerization method in which a plasma source generatesa gas discharge that provides energy to activate a cross-linkingreaction within a gaseous, aerosolized, or liquid monomeric precursor(e.g., vinylpyridine). This converts the monomeric precursor to apolymeric coating that may be deposited on the microneedle array to aspecified thickness, thereby creating a thin film with the desiredthickness and porosity required to restrict the diffusion of an analyteof interest to the biorecognition layer 1614.

Furthermore, in some variations, a diffusion-limiting layer may appliedby electrophoretic or dielectrophoretic deposition, such as exampletechniques described in U.S. Pat. No. 10,092,207, which is incorporatedherein in its entirety by this reference.

Counter Electrode

Anodization: In some variations, the counter electrode material mayundergo an anodization treatment using an amperometry approach in whichthe electrode constituent(s) assigned for the counter electrode functionis subject to a fixed high anodic potential or a suitable amount of timein a moderate-strength acid solution. Exemplary parameters and otherspecifics of the anodization process for the counter electrode may besimilar to that described above for the working electrode. Similarly,anodization for the counter electrode may alternatively use a coulometryapproach as described above.

Activation: In some variations, following the anodization process, thecounter electrode constituents may be subjected to a cyclically-scannedpotential waveform in an activation process using cyclic voltammetry. Insome variations, the activation process may be similar to that describedabove for the working electrode.

Roughening: Furthermore, in some variations, the counter electrodesurface may be electrochemically roughened in order to enhance thecurrent-sinking or current-sourcing capacity of this electrodecontingent. The electrochemical roughening process may be similar tothat described above for the working electrode. Additionally oralternatively, in some variations as described above, elemental platinummetal may deposited on the electrode to form or deposit a platinum blacklayer 1623.

Reference Electrode

Anodization: Like the working and counter electrodes as described above,the reference electrode may undergo an anodization treatment using anamperometry approach in which the electrode constituent(s) assigned forthe counter electrode function is subject to a fixed high anodicpotential or a suitable amount of time in a moderate-strength acidsolution. Exemplary parameters and other specifics of the anodizationprocess for the counter electrode may be similar to that described abovefor the working electrode. Similarly, anodization for the counterelectrode may

Activation: Following the anodization process, the reference electrodeconstituents may be subjected to a cyclically-scanned potential waveformin an activation process using cyclic voltammetry. In some variations,the activation process may be similar to that described above for theworking electrode.

Functionalization: Following the activation process, the referenceelectrode constituents may be functionalized. Assuming that thereference electrode contingent of the microneedle array has undergonethe aforementioned steps, a fixed anodic potential (e.g., between+0.4-+1.0 V vs. Ag/AgCl reference electrode) may be applied for acertain suitable duration (e.g., between about 10 sec and about 10 min)in an aqueous solution. Alternatively, the reference electrode issubject to a fixed anodic potential (e.g., between about +0.4 to about+1.0 V vs. Ag/AgCl reference electrode) until a certain amount of chargehas passed (e.g., 0.01 mC-10 mC) in an aqueous solution. In somevariations, the aqueous solution may include a monomeric precursor to aconducting polymer and a charged dopant counter ion or material (e.g.,poly(styrene sulfonate)) carrying an opposing charge. In this process, athin film (e.g., between about 10 nm and about 10,000 nm) of aconducting polymer with a dispersed counter ion or material may begenerated on the reference electrode surface. This creates asurface-immobilized, solid-state redox couple with a stablethermodynamic potential. In some variations, the conducting polymer mayinclude one or more of aniline, pyrrole, acetylene, phenylene, phenylenevinylene, phenylene diamine, thiophene, 3,4-ethylenedioxythiophene, andaminophenylboronic acid.

In some alternative embodiments, a native iridium oxide film (e.g., IrO₂or Ir₂O₃ or IrO₄) may be electrochemically grown on an iridium electrodesurface in an oxidative process. This also creates a stable redoxcouple, as discussed above.

Furthermore, in some variations the reference electrode surface may beelectrochemically roughened in order to enhance adhesion of thesurface-immobilized redox couple. The electrochemical roughening processmay be similar to that described above for the working electrode.Additionally or alternatively, in some variations as described above,elemental platinum metal may deposited on the electrode to form ordeposit a platinum black layer 1633.

Other features and techniques for forming the reference electrode may besimilar to that described in, for example, U.S. Patent Pub. No.2019/0309433, which was incorporated above by reference.

Microneedle Array Configurations

Multiple microneedles (e.g., any of the microneedle variations describedherein, each of which may have a working electrode, counter electrode,or reference electrode as described above) may be arranged in amicroneedle array. Considerations of how to configure the microneedlesinclude factors such as desired insertion force for penetrating skinwith the microneedle array, optimization of electrode signal levels andother performance aspects, manufacturing costs and complexity, etc.

For example, the microneedle array may include multiple microneedlesthat are spaced apart at a predefined pitch (distance between the centerof one microneedle to the center of its nearest neighboringmicroneedle). In some variations, the microneedles may be spaced apartwith a sufficient pitch so as to distribute force (e.g., avoid a “bed ofnails” effect) that is applied to the skin of the user to cause themicroneedle array to penetrate the skin. As pitch increases, forcerequired to insert the microneedle array tends to decrease and depth ofpenetration tends to increase. However, it has been found that pitchonly begins to affect insertion force at low values (e.g., less thanabout 150 μm). Accordingly, in some variations the microneedles in amicroneedle array may have a pitch of at least 200 μm, at least 300 μm,at least 400 μm, at least 500 μm, at least 600 μm, at least 700 μm, orat least 750 μm. For example, the pitch may be between about 200 μm andabout 800 μm, between about 300 μm and about 700 μm, or between about400 μm and about 600 μm. In some variations, the microneedles may bearranged in a periodic grid, and the pitch may be uniform in alldirections and across all regions of the microneedle array.Alternatively, the pitch may be different as measured along differentaxes (e.g., X, Y directions) and/or some regions of the microneedlearray may include a smaller pitch while other may include a largerpitch.

Furthermore, for more consistent penetration, microneedles may be spacedequidistant from one another (e.g., same pitch in all directions). Tothat end, in some variations, the microneedles in a microneedle arraymay be arranged in a hexagonal configuration as shown in FIG. 17 .Alternatively, the microneedles in a microneedle array may arranged in arectangular array (e.g., square array), or in another suitablesymmetrical manner

Another consideration for determining configuration of a microneedlearray is overall signal level provided by the microneedles. Generally,signal level at each microneedle is invariant of the total number ofmicroneedle elements in an array. However, signal levels can be enhancedby electrically interconnecting multiple microneedles together in anarray. For example, an array with a large number of electricallyconnected microneedles is expected to produce a greater signal intensity(and hence increased accuracy) than one with fewer microneedles.However, a higher number of microneedles on a die will increase die cost(given a constant pitch) and will also require greater force and/orvelocity to insert into skin. In contrast, a lower number ofmicroneedles on a die may reduce die cost and enable insertion into theskin with reduced application force and/or velocity. Furthermore, insome variations a lower number of microneedles on a die may reduce theoverall footprint area of the die, which may lead to less unwantedlocalized edema and/or erythema. Accordingly, in some variations, abalance among these factors may be achieved with a microneedle arrayincluding 37 microneedles as shown in FIG. 17 or a microneedle arrayincluding 7 microneedles are shown in FIGS. 29A and 29B. However, inother variations there may be fewer microneedles in an array (e.g.,between about 5 and about 35, between about 5 and about 30, betweenabout 5 and about 25, between about 5 and about 20, between about 5 andabout 15, between about 5 and about 100, between about 10 and about 30,between about 15 and about 25, etc.) or more microneedles in an array(e.g., more than 37, more than 40, more than 45, etc.).

Additionally, as described in further detail below, in some variationsonly a subset of the microneedles in a microneedle array may be activeduring operation of the analyte monitoring device. For example, aportion of the microneedles in a microneedle array may be inactive(e.g., no signals read from electrodes of inactive microneedles). Insome variations, a portion of the microneedles in a microneedle arraymay be activated at a certain time during operation and remain activefor the remainder of the operating lifetime of the device. Furthermore,in some variations, a portion of the microneedles in a microneedle arraymay additionally or alternatively be deactivated at a certain timeduring operation and remain inactive for the remainder of the operatinglifetime of the device.

In considering characteristics of a die for a microneedle array, diesize is a function of the number of microneedles in the microneedlearray and the pitch of the microneedles. Manufacturing costs are also aconsideration, as a smaller die size will contribute to lower cost sincethe number of dies that can be formed from a single wafer of a givenarea will increase. Furthermore, a smaller die size will also be lesssusceptible to brittle fracture due to the relative fragility of thesubstrate.

Furthermore, in some variations, microneedles at the periphery of themicroneedle array (e.g., near the edge or boundary of the die, near theedge or boundary of the housing, near the edge or boundary of anadhesive layer on the housing, along the outer border of the microneedlearray, etc.) may be found to have better performance (e.g., sensitivity)due to better penetration compared to microneedles in the center of themicroneedle array or die. Accordingly, in some variations, workingelectrodes may be arranged largely or entirely on microneedles locatedat the periphery of the microneedle array, to obtain more accurateand/or precise analyte measurements.

FIG. 17 depicts an illustrative schematic of 37 microneedles arranged inan example variation of a microneedle array. The 37 microneedles may,for example, be arranged in a hexagonal array with an inter-needlecenter-to-center pitch of about 750 μm (or between about 700 μm andabout 800 μm, or between about 725 μm and about 775 μm) between thecenter of each microneedle and the center of its immediate neighbor inany direction. FIG. 18A depicts an illustrative schematic of an examplevariation of a die including the microneedle arrangement shown in FIG.17 . Example dimensions of the die (e.g., about 4.4 mm by about 5.0 mm)and the microneedle array are shown in FIG. 18B.

FIGS. 29A and 29B depict perspective views of an illustrative schematicof seven microneedles 2910 arranged in an example variation of amicroneedle array 2900. The seven microneedles 2910 are arranged in ahexagonal array on a substrate 2902. As shown in FIG. 29A, theelectrodes 2920 are arranged on distal portions of the microneedles 2910extending from a first surface of the substrate 2902. As shown in FIG.29B, proximal portions of the microneedles 2910 are conductivelyconnected to respective backside electrical contacts 2930 on a secondsurface of the substrate 2902 opposite the first surface of thesubstrate 2902. FIGS. 30A and 30B depict plan and side views of anillustrative schematic of a microneedle array similar to microneedlearray 2900. As shown in FIGS. 30A and 30B, the seven microneedles arearranged in a hexagonal array with an inter-needle center-to-centerpitch of about 750 μm between the center of each microneedle and thecenter of its immediate neighbor in any direction. In other variationsthe inter-needle center-to-center pitch may be, for example, betweenabout 700 μm and about 800 μm, or between about 725 μm and about 775 μm.The microneedles may have an approximate outer shaft diameter of about170 μm (or between about 150 μm and about 190 μm, or between about 125μm and about 200 μm) and a height of about 500 μm (or between about 475μm and about 525 μm, or between about 450 μm and about 550 μm).

Furthermore, the microneedle arrays described herein may have a highdegree of configurability concerning where the working electrode(s),counter electrode(s), and reference electrode(s) are located within themicroneedle array. This configurability may be facilitated by theelectronics system.

In some variations, a microneedle array may include electrodesdistributed in two or more groups in a symmetrical or non-symmetricalmanner in the microneedle array, with each group featuring the same ordiffering number of electrode constituents depending on requirements forsignal sensitivity and/or redundancy. For example, electrodes of thesame type (e.g., working electrodes) may be distributed in a bilaterallyor radially symmetrical manner in the microneedle array. For example,FIG. 19A depicts a variation of a microneedle array 1900A including twosymmetrical groups of seven working electrodes (WE), with the twoworking electrode groups labeled “1” and “2”. In this variation, the twoworking electrode groups are distributed in a bilaterally symmetricalmanner within the microneedle array. The working electrodes aregenerally arranged between a central region of three referenceelectrodes (RE) and an outer perimeter region of twenty counterelectrodes (CE). In some variations, each of the two working electrodegroups may include seven working electrodes that are electricallyconnected amongst themselves (e.g., to enhance sensor signal).Alternatively, only a portion of one or both of the working electrodegroups may include multiple electrodes that are electrically connectedamongst themselves. As yet another alternative, the working electrodegroups may include working electrodes that are standalone and notelectrically connected to other working electrodes. Furthermore, in somevariations the working electrode groups may be distributed in themicroneedle array in a non-symmetrical or random configuration.

As another example, FIG. 19B depicts a variation of a microneedle array1900B including four symmetrical groups of three working electrodes(WE), with the four working electrode groups labeled “1”, “2”, “3”, and“4.” In this variation, the four working electrode groups aredistributed in a radially symmetrical manner in the microneedle array.Each working electrode group is adjacent to one of two referenceelectrode (RE) constituents in the microneedle array and arranged in asymmetrical manner. The microneedle array also includes counterelectrodes (CE) arranged around the perimeter of the microneedle array,except for two electrodes on vertices of the hexagon that are inactiveor may be used for other features or modes of operation.

In some variations, only a portion of microneedle array may includeactive electrodes. For example, FIG. 19C depicts a variation of amicroneedle array 1900C with 37 microneedles and a reduced number ofactive electrodes, including four working electrodes (labeled “1”, “2”,“3”, and “4”) in a bilaterally symmetrical arrangement, twenty-twocounter electrodes, and three reference electrodes. The remaining eightelectrodes in the microneedle array are inactive. In the microneedlearray shown in FIG. 19C, each of the working electrodes is surrounded bya group of counter electrodes. Two groups of such clusters of workingelectrodes and counter electrodes are separated by a row of the threereference electrodes.

As another example, FIG. 19D depicts a variation of a microneedle array1900D with 37 microneedles and a reduced number of active electrodes,including four working electrodes (labeled “1”, “2”, “3”, and “4”) in abilaterally symmetrical arrangement, twenty counter electrodes, andthree reference electrodes, where the remaining ten electrodes in themicroneedle array are inactive.

As another example, FIG. 19E depicts a variation of a microneedle array1900E with 37 microneedles and a reduced number of active electrodes,including four working electrodes (labeled “1”, “2”, “3”, and “4”),eighteen counter electrodes, and two reference electrodes. The remainingthirteen electrodes in the microneedle array are inactive. The inactiveelectrodes are along a partial perimeter of the overall microneedlearray, thereby reducing the effective size and shape of the activemicroneedle arrangement to a smaller hexagonal array. Within the activemicroneedle arrangement, the four working electrodes are generally in aradially symmetrical arrangement, and each of the working electrodes issurrounded by a group of counter electrodes.

FIG. 19F depicts another example variation of a microneedle array 1900Fwith 37 microneedles and a reduced number of active electrodes,including four working electrodes (labeled “1”, “2”, “3”, and “4”), twocounter electrodes, and one reference electrode. The remaining thirtyelectrodes in the microneedle array are inactive. The inactiveelectrodes are arranged in two layers around the perimeter of theoverall microneedle array, thereby reducing the effective size and shapeof the active microneedle arrangement to a smaller hexagonal arraycentered around the reference electrode. Within the active microneedlearrangement, the four working electrodes are in a bilaterallysymmetrical arrangement and the counter electrodes are equidistant fromthe central reference electrode.

FIG. 19G depicts another example variation of a microneedle array 1900Gwith 37 microneedles and a reduced number of active electrodes. Theactive electrodes in microneedle array 1900G are arranged in a similarmanner as that in microneedle array 1900F shown in FIG. 19F, except thatthe microneedle array 1900G includes one counter electrode and tworeference electrodes, and the smaller hexagonal array of activemicroneedles is centered around the counter electrode. Within the activemicroneedle arrangement, the four working electrodes are in abilaterally symmetrical arrangement and the reference electrodes areequidistant from the central counter electrode.

FIG. 19H depicts another example variation of a microneedle array 1900Hwith 7 microneedles. The microneedle arrangement contains twomicroneedles assigned as independent working electrodes (1 and 2), acounter electrode contingent comprised of 4 microneedles, and a singlereference electrode. There is bilateral symmetry in the arrangement ofworking and counter electrodes, which are equidistant from the centralreference electrode. Additionally, the working electrodes are arrangedas far as possible from the center of the microneedle array (e.g., atthe periphery of the die or array) to take advantage of a location wherethe working electrodes are expected to have greater sensitivity andoverall performance.

FIG. 19I depicts another example variation of a microneedle array 1900Iwith 7 microneedles. The microneedle arrangement contains fourmicroneedles assigned as two independent groupings (1 and 2) of twoworking electrodes each, a counter electrode contingent comprised of 2microneedles, and a single reference electrode. There is bilateralsymmetry in the arrangement of working and counter electrodes, which areequidistant from the central reference electrode. Additionally, theworking electrodes are arranged as far as possible from the center ofthe microneedle array (e.g., at the periphery of the die or array) totake advantage of a location where the working electrodes are expectedto have greater sensitivity and overall performance.

FIG. 19J depicts another example variation of a microneedle array 1900Jwith 7 microneedles. The microneedle arrangement contains fourmicroneedles assigned as independent working electrodes (1, 2, 3, and4), a counter electrode contingent comprised of 2 microneedles, and asingle reference electrode. There is bilateral symmetry in thearrangement of working and counter electrodes, which are equidistantfrom the central reference electrode. Additionally, the workingelectrodes are arranged as far as possible from the center of themicroneedle array (e.g., at the periphery of the die or array) to takeadvantage of a location where the working electrodes are expected tohave greater sensitivity and overall performance.

While FIGS. 19A-19J illustrate example variations of microneedle arrayconfigurations, it should be understood that these figures are notlimiting and other microneedle configurations (including differentnumbers and/or distributions of working electrodes, counter electrodes,and reference electrodes, and different numbers and/or distributions ofactive electrodes and inactive electrodes, etc.) may be suitable inother variations of microneedle arrays.

Warm-Up

Many implanted electrochemical sensors require a “warm-up” time, or timefor the sensor to attain a stable signal value following implantation.This process has origins in both physiology and sensor dynamics.However, various aspects of analyte monitoring devices described hereinare configured to mitigate factors contributing to warm-up time, therebyallowing the analyte monitoring devices described herein to havesignificantly shorter warm-up times compared to traditional CGM systems.For example, the analyte monitoring devices described herein may have awarm-up time of about 30 minutes or less (e.g., between about 10 minutesand about 30 minutes, between about 15 minutes and about 30 minutes,between about 20 minutes and about 30 minutes, between about 25 minutesand about 30 minutes), about 45 minutes or less, about 60 minutes orless, about 90 minutes or less, or about 120 minutes or less. In somevariations, following a warm-up period, the analyte monitoring devicemay calibration during a calibration period.

Wound response: For example, the implantation of a sensor creates awound response due to the localization disruption, displacement, anddestruction of tissue. The larger the sensor, or the deeper the implant,the more prolific the wound response. Accordingly, there is a compellingrationale to miniaturize the sensor to elicit an attenuated woundresponse, which would result in more rapid warm-up.

Protein adsorption: Additionally, following implantation of a sensor,the foreign body response is immediately instigated. The foreign bodyresponse includes a complex biochemical cascade that aims to encapsulatethe foreign material with cellular matter. Hydrophobic surfaces tend tobe subject to adsorption of endogenous proteins very rapidly followingimplant; this is referred to as biofouling. Hydrophilic surfaces, on theother hand, resist biofouling due to high water content. Human serumalbumin (HSA) is the predominant protein in the dermal interstitialfluid, constituting about 60% of total protein, and maintains a negativecharge at physiological pH. When the sensor is polarized with a positivepotential (as in some variation of the analyte monitoring device),endogenous HSA is subject to electric drift and charge attraction to thepositive (working) electrode of the sensor. This can give rise to anincreased propensity for the sensor surface to biofoul. This is therationale behind the implementation of either a hydrophilic diffusionlimiting layer or outer biocompatible layer to effectively conceal thesensor from being recognized as a foreign body, as described in furtherdetail above.

As described herein, the analyte monitoring device reduces the influenceof the above physiological factors on warm-up time due to, for example,the shallow nature of the implant, the minimal volume of tissuedisplaced (e.g., up to about two orders of magnitude lower than currentCGM systems, such as between about 100 and about 1000 times less tissuedisplaced, or between about 200 and about 600 times less tissuedisplaced compared to current CGM systems), the minimal amount of traumato said tissue during implantation, and the lack of permeation of thevasculature deeper in the reticular dermis, which, when perturbed, caninstigate a more prolific wound response that will engender anaccelerated effort to encapsulate the implant, as is the case withcompeting wire-implanted CGM systems.

Attainment of equilibrium: One example of the effect of sensor dynamicson warm-up time relates to the attainment of equilibrium. Anelectrochemical sensor requires a finite amount of time to achieveequilibrium when used in a new environment. This is typically associatedwith the establishment of thermodynamic equilibrium due to an adsorbedsurface layer of ions at the electrodes. As the reference electrode inmost implantable electrochemical sensors does not employ an internalfilling solution with a redox couple that is sealed from the rest of theelectrochemical cell, this reference electrode must attain equilibriumwith its surroundings in order to establish a stable referencepotential.

Hydration of sensor layers: The electrode sensor layers must be immersedin an aqueous environment to function properly. The resulting hydrationprocess may activate the electrode's polymer layer(s) and biorecognitionelement(s) and allows them to rearrange and return to their nativeactive tertiary structure, which is primarily responsible for theiractivity or unique properties. This process is often known as sensor‘wetting’ and allows the medium in which the sensing operation occurs tointercalate the sensor layers to a sufficient extent.

Decaying of the non-Faradaic response: The biasing (application of avoltage) of an electrochemical sensor will cause a double layer of ionsto form at the electrode surface. This process requires a finite amountof time due to the charging of the adsorbed species on the electrodesurface. This gives rise to a double layer capacitance. The non-Faradaictime constant is equal to the product of the said double layercapacitance and the solution resistance. Oftentimes, the non-Faradicresponse (electrical current) decays to negligible levels more rapidlythan other physical phenomena and it is often not the rate-limiting stepin the warm-up process. Once the non-Faradaic response decays tonegligible levels, the Faradaic response ensues, which is reflective ofthe electrochemical/redox reaction of interest

As described herein, the analyte monitoring device may reduce theinfluence of sensor dynamics on warm-up time due to, for example, theimplementation thin membrane layers (on the order of 10 nm-5000 nm),which allow the layers to hydrate more rapidly than competingimplantable CGM systems. Moreover and owing to the diminutive dimensionsof the electrodes described herein (e.g., geometric surface area of theworking electrode(s)), the non-Faradaic response transpires for shorterdurations (due to reduced double layer capacitance and hence charging ofthe double layer). In some variations, a high-potential (e.g., >0.75V)bias for a limited period of time following application of the device toskin may further expedite burn-in or warm-up of the sensor to achieveequilibrium and stable signal levels.

Signal Latency

Typically, implanted electrochemical sensors also experience a delay, orsignal latency, in attaining a stable signal value following changes inanalyte levels. This signal latency is a function of various factors. Ata high level, latency is a function of 3 distinct effects: (1)diffusional lag (amount of time that is required for a molecule ofanalyte to diffuse from the capillary (source) to the sensor surface,(2) diffusional limitation imposed by the sensor membrane/layerarchitecture on the sensors, and (3) algorithmic processing of data(averaging, filtering, signal denoising, and other signal processingmeasures), which often results in a group delay. However, variousaspects of the analyte monitoring devices described herein minimizethese factors contributing to signal latency, thereby resulting in afaster response time for analyte measurements.

As described above, one significant advantage of the analyte monitoringdevices described herein is that location of sensor placement. Becausethe electrode surface is implanted at a location in such close proximity(e.g., within a few hundred micrometers or less) to the dense andwell-perfused capillary bed of the reticular dermis, the diffusional lagis negligible. This is a significant advantage over conventional analytesensors, which reside in the very poorly vascularized adipose tissuebeneath the dermis and hence the diffusion distance, and resultingdiffusional latency, from the vasculature in the dermis is substantial(e.g., typically 5-20 minutes).

Additionally, as the films deposited on the electrode sensor surface useelectrodeposition methods, the precise thickness of said films can becontrolled to a highly precise degree. For example, theelectrodeposition methods of forming the sensor surface enableconsistent, controlled creation of thin film layers that may reducediffusional lag. Moreover, the spatial localization of the thin filmlayers to the sensing electrode allows the realization of thinner andless diffusionally resistive films, which further reduce latency due todiffusion of the analyte from the other film surface to thebiorecognition layer.

Furthermore, the high level of redundancy (parallel channels of analytemeasurement) afforded by the microneedle array allows for higherfidelity measurement and less reliance on the algorithm to interpolatesensor readings, which imparts greater reduced delay or latency.

Electronics System

As shown in the schematic of FIG. 2A of an analyte monitoring device110, the electronics system 120 may be integrated within the housing112, such that the electronics system 120 may be combined with sensingelements (e.g., microneedle array) as part of a single unit, in contrastto traditional CGM systems, which typically incorporate components inmultiple physically distinct units. Further details of an examplevariation of an electronics system 120 are described below.

PCBs

In some variations, the analyte monitoring device may include one ormore PCBs. For example, the analyte monitoring device may include atleast one PCB in the sensor assembly 320 that includes the microneedlearray, and at least one device PCB 350 as shown in FIG. 3E.

For example, as shown in FIGS. 3F-3I, a sensor assembly 320 may includea sensor standoff PCB 322 coupled to a connecting PCB 324. Themicroneedle array 330 may be attached to the sensor standoff PCB 322(e.g., FR-4, PTFE, Rogers 4350B), such as through a soldering processcombined with an epoxy underfill for mechanical strength. In somevariations, an epoxy skirt may be deposited along the edges of thesilicon microneedle array 330 to relieve the sharp edges from thesilicon dicing processes described above. The epoxy may also provide atransition from the edge of the silicon substrate of the microneedlearray silicon to the edge of the PCB 322. Alternatively, this epoxy maybe replaced or supplemented by a rubber gasket or the like.

As shown in FIG. 3J, the sensor standoff PCB 322 may function as astandoff that at least in part determines the desired distance to whichthe microneedle array 330 protrudes from the housing 310. Accordingly,the standoff height of the sensor standoff PCB 322 may be selected tohelp ensure that the microneedle array 330 is inserted properly into auser's skin. During needle insertion, the bottom surface of the housing310 will act as a stop for needle insertion. If the sensor standoff PCB322 has a reduced height and its lower surface is flush or nearly flushwith the bottom surface of the housing, then the housing 310 may preventthe microneedle array 330 from being fully inserted into the skin.However, increasing the standoff height may lead to more pressure of themicroneedle array on the skin during microneedle insertion, which canlead to dermatological irritation and/or erythema (redness of the skin).

The sensor standoff PCB 322 may be secured to the housing 310 and/orsecured within the stack up inside the housing, such as with suitablefasteners or the like. For example, as shown in FIGS. 3H-3J, the sensorstandoff PCB 322 (with the microneedle array 330) may be coupled to afirst side of the connecting PCB 324, while a second opposite side ofthe connecting PCB 324 may in turn be coupled to an interposer PCBconnector 326. As shown in FIG. 3J, the interposer PCB connector 326 maybe communicatively coupled to the device PCB 350, such as for signalprocessing as described below. Accordingly, signals from the microneedlearray 330 may be communicated through the sensor standoff PCB 322 and tothe device PCB via the sensor standoff PCB 322, connecting PCB 324, andinterposer PCB connector 326. However, in some variations the analytemonitoring device may include fewer PCBs. For example, in somevariations, the sensor assembly 320 may omit the sensor standoff PCB322, such that the microneedle array 330 may directly communicateelectrically to the connecting PCB 324 (or directly to the device PCB350).

Additionally or alternatively, in some variations at least one of thePCBs in the sensor assembly 320 may include or be coupled to one or moreadditional sensors in combination with the microneedle array 330. Forexample, the sensor assembly 320 may include a temperature sensor (e.g.,thermistor, resistance temperature detector, thermocouple, bandgapreference, non-contact temperature sensor, etc.). In some variations,temperature measurement may additionally or alternatively be performedby one or more analyte-insensitive electrodes in the microneedle array.

In some variations, the sensor standoff PCB 322 may be between about0.05 inches and about 0.15 inches, or between about 0.093 inches andabout 0.127 inches in thickness. The sensor standoff PCB 322, in somevariations, may include one or a plurality of conductivethrough-substrate vias configured to route electrical signals from ananterior surface of the PCB to a posterior surface of the PCB. In somevariations, the sensor standoff PCB 322 may comprise a semiconductor(e.g., silicon) with conductive through-substrate vias configured toroute electrical signals from an anterior surface of the semiconductorto a posterior surface of the semiconductor. In yet other variations,the microneedle array 330 may be mounted directly to the PCB 324,without the sensor standoff PCB 322.

Analog Front End

In some variations, the electronics system of the analyte monitoringdevice may include an analog front end. The analog front end may includesensor circuitry (e.g., sensor circuitry 124 as shown in FIG. 2A) thatconverts analog current measurements to digital values that can beprocessed by the microcontroller. The analog front end may, for example,include a programmable analog front end that is suitable for use withelectrochemical sensors. For example, the analog front end may include aMAX30131, MAX30132, or MAX30134 component (which have 1, 2, and 4channel, respectively), available from Maxim Integrated (San Jose,Calif.), which are ultra-low power programmable analog front ends foruse with electrochemical sensors. The analog front end may also includean AD5940 or AD5941 component, available from Analog Devices (Norwood,Mass.), which are high precision, impedance and electrochemical frontends. Similarly, the analog front end may also include an LMP91000,available from Texas Instruments (Dallas, Tex.), which is a configurableanalog front end potentiostat for low-power chemical sensingapplications. The analog front end may provide biasing and a completemeasurement path, including the analog to digital converters (ADCs).Ultra-low power may allow for the continuous biasing of the sensor tomaintain accuracy and fast response when measurement is required for anextended duration (e.g. 7 days) using a body-worn, battery-operateddevice.

In some variations, the analog front end device may be compatible withboth two and three terminal electrochemical sensors, such as to enableboth DC current measurement, AC current measurement, and electrochemicalimpedance spectroscopy (EIS) measurement capabilities. Furthermore, theanalog front end may include an internal temperature sensor andprogrammable voltage reference, support external temperature monitoringand an external reference source and integrate voltage monitoring ofbias and supply voltages for safety and compliance.

In some variations, the analog front end may include a multi-channelpotentiostat to multiplex sensor inputs and handle multiple signalchannels. For example, the analog front end may include a multi-channelpotentiostat such as that described in U.S. Pat. No. 9,933,387, which isincorporated herein in its entirety by this reference.

In some variations, the analog front end and peripheral electronics maybe integrated into an application-specific integrated circuit (ASIC),which may help reduce cost, for example. This integrated solution mayinclude the microcontroller described below, in some variations.

Microcontroller

In some variations, the electronics system of the analyte monitoringdevice may include at least one microcontroller (e.g., controller 122 asshown in FIG. 2A). The microcontroller may include, for example, aprocessor with integrated flash memory. In some variations, themicrocontroller in the analyte monitoring device may be configured toperform analysis to correlate sensor signals to an analyte measurement(e.g., glucose measurement). For example, the microcontroller mayexecute a programmed routine in firmware to interpret the digital signal(e.g., from the analog front end), perform any relevant algorithmsand/or other analysis, and route processed data to and/or from thecommunication module. Keeping the analysis on-board the analytemonitoring device may, for example, enable the analyte monitoring deviceto broadcast analyte measurement(s) to multiple devices (e.g., mobilecomputing devices such as a smartphone or smartwatch, therapeuticdelivery systems such as insulin pens or pumps, etc.) in parallel, whileensuring that each connected device has the same information.

In some variations, the microcontroller may be configured to activateand/or inactivate the analyte monitoring device on one or more detectedconditions. For example, the device may be configured to power on theanalyte monitoring device upon insertion of the microneedle array intoskin. This may, for example, enable a power-saving feature in which thebattery is disconnected until the microneedle array is placed in skin,at which time the device may begin broadcasting sensor data. Such afeature may, for example, help improve the shelf life of the analytemonitoring device and/or simplify the analyte monitoring device-externaldevice pairing process for the user.

FIG. 25 illustrates a schematic of an example variation of circuitryenabling the above-described activation of the analyte monitoring deviceupon insertion. Generally, upon penetration of the stratum corneum ofthe skin and positioning of the electrode at the distal tip of themicroneedle constituents in the highly electrolytic dermal interstitialfluid, the resistance of “Sensor Detect” reduces to a significantextent, thereby activating the p-channel MOSFET Q401. Once Q401 isturned on, the battery voltage VBAT flows to VDD_IN and that providespower for the device. When the microcontroller powers on, the firstroutine it executes is to set “PwrEnable” high, hence keeping the devicethe device powered by pulling the gate of Q401 low through Q402. This isperformed in order to mitigate a scenario wherein the microneedles arenot keeping contact with the skin. If the device has been subject to afalse start, a high resistance on “Sensor_Detect” should be present andthe microprocessor can take “PwrEnable” low, thereby removing power tothe device (and inactivating the device). Other example variations ofstructures and methods for activating and/or inactivating an analytemonitoring device are described in further detail in U.S. patentapplication Ser. No. 16/051,398, which is incorporated herein in itsentirety by this reference.

Additionally or alternatively, the microcontroller may be configured toactively confirm the insertion of the microneedle array into skin basedon sensor measurements performed with the microneedle array. Forexample, after two or more microneedles in the microneedle array arepresumed to have been inserted into skin, a fixed or time-varyingelectrical potential or current may be applied to those microneedles. Ameasurement result (e.g., electrical potential or current value) of asignal generated between the electrodes of the inserted microneedles ismeasured, and then compared to a known reference value to corroboratesuccessful insertion of the microneedle array into the skin. Thereference value may, for example, include a voltage, a current, aresistant, a conductance, a capacitance, an inductance and/or animpedance. Other example variations of structures and methods foractivating and/or inactivating an analyte monitoring device aredescribed in further detail in U.S. patent application Ser. No.16/051,398 which was incorporated above by reference.

In some variations, the microcontroller may utilize an 8-bit, 16-bit,32-bit, or 64-bit data structure. Suitable microcontroller architecturesinclude ARM® and RISC® architectures, and flash memory may be embeddedor external to the microcontroller for suitable data storage. In somevariations the microcontroller may be a single core microcontroller,while in some variations the microcontroller may be a multi-core (e.g.,dual core) microcontroller which may enable flexible architectures foroptimizing power and/or performance within the system. For example, thecores in the microcontroller may include similar or differingarchitectures. For example, in an example variation, the microcontrollermay be a dual core microcontroller including a first core with a highperformance and high power architecture, and a second core with a lowperformance and low power architecture. The first core may function as a“workhorse” in that it may be used to process higher performancefunctions (e.g., sensor measurements, algorithmic calculations, etc.),while the second core may be used to perform lower performance functions(e.g., background routines, data transmission, etc.). Accordingly, thedifferent cores of the microcontroller may be run at different dutycycles (e.g., the second core for lower performance functions may be runat a higher duty cycles) optimized for their respective functions,thereby improving overall power efficiency. Additionally oralternatively, in some variations the microcontroller may includeembedded analog circuitry, such as for interfacing with additionalsensor(s) and/or the microneedle array. In some variations, themicrocontroller may be configured to operate using a 0.8V-5V powersource, such as a 1.2V-3V power source.

Communication Module

In some variations, the electronics system of the analyte monitoringdevice may include at least one communication module (e.g.,communication module 126 as shown in FIG. 2A), such as a wirelesscommunication module to communicate with one or more devices. Forexample, the communication module may include a wireless transceiverthat is integrated into the microcontroller device. However, theelectronics system may additionally or alternatively include acommunication module that is separate from the microcontroller device.In some variations, the communication module may communicate viawireless network (e.g., through Bluetooth, NFC, WiFi, RFID, or any typeof data transmission that is not connected by cables). For example,devices may directly communicate with each other in pairwise connection(1:1 relationship, i.e. unicasting), or in a hub-spoke or broadcastingconnection (“one to many” or 1:m relationship, i.e. multicasting). Asanother example, the devices may communicate with each other throughmesh networking connections (e.g., “many to many”, or m:m relationships,or ad-hoc), such as through Bluetooth mesh networking. Wirelesscommunication may use any of a plurality of communication standards,protocols, and technologies, including but not limited to, Global Systemfor Mobile Communications (GSM), Enhanced Data GSM Environment (EDGE),high-speed downlink packet access (HSDPA), high-speed uplink packetaccess (HSUPA), Evolution, Data-Only (EV-DO), HSPA, HSPA+, Dual-CellHSPA (DC-HSPDA), long term evolution (LTE), near field communication(NFC), wideband code division multiple access (W-CDMA), code divisionmultiple access (CDMA), time division multiple access (TDMA), Bluetooth,Wireless Fidelity (WiFi) (e.g., IEEE 802.11a, IEEE 802.11b, IEEE802.11g, IEEE 802.11n, and the like), or any other suitablecommunication protocol. Some wireless network deployments may combinenetworks from multiple cellular networks or use a mix of cellular,Wi-Fi, and satellite communication. In an example variation, thecommunication module may include a wireless transceiver integrated intothe microcontroller and including a Bluetooth Low Energy compatibleradio that complies with the Bluetooth Special Interest Group 5.0specification.

The communication module may further include or be coupled to one ormore antennas (e.g., antenna 128 as shown in FIG. 2A). For example, theelectronics system may include a chip antenna mounted on the PCB, or anantenna implemented directly onto the PCB, which may provide betterrange while reducing cost and complexity. In some variations, a userwearing the analyte monitoring device 110 may function as an antenna(e.g., antenna 128). For example, the antenna input/output 128 of thecommunication module 126 may be electrically connected to a singlemicroneedle or plurality of microneedles, which are inserted into thewearer's skin (e.g., similar to microneedle array 140 shown in FIG. 2B).This may increase the effective cross-sectional area of the antenna,provide for an adequate impedance match between the antenna input/outputof the communication module and free space, and/or help improveoperational metrics such as antenna gain, antenna diversity,omni-directionality, and communication module receiversensitivity/transmitter efficiency.

Devices can come in and out of range from the communication module toconnect and reconnect so that the user is able to seamlessly connect andtransfer information between devices. In some variations, themicrocontroller on each analyte monitoring device may have a uniqueserial number, which enables tracking of specific analyte monitoringdevices during production and/or field use.

Additional Sensors

As described above, in some variations, the analyte monitoring devicemay include one or more sensors in addition the microneedle array. Forexample, the analyte monitoring device may include one or moretemperature sensors configured to measure skin temperature, therebyenabling temperature compensation for the analyte sensor(s). Forexample, in some variations, a temperature sensor (e.g., thermistor,RTD, semiconductor junction, bimetallic sensor, thermopile sensor) maybe coupled to the device PCB within the housing such that thetemperature sensor is arranged near a skin-facing portion or bottomportion of the housing 112. The housing may be thinned to reduce thermalresistance and improve heat transfer and hence measurement accuracy.Additionally or alternatively, a thermally conductive material maythermally couple a surface-mount temperature sensor to the user's skin.In variations in which the temperature sensor is coupled to the devicePCB near the microneedle array die substrate, the thermally conductivematerial may, for example, be molded as a skirt to relieve the sharpedges of the die and wrap along the edges of the die and along thesurface of the main PCB.

In some variations, the temperature sensor may be employed to develop aglucose interpolation characteristic based on measured current and an apriori sensitivity (e.g., nA/mM or pA/mg/dL). In thetemperature-invariant case, the electrical current characteristic can bemodeled by the following relation: y=m_(G)[G] where y is the measuredcurrent, m_(G) is the glucose sensitivity, and [G] is the interpolatedglucose concentration. In some cases, such as the incorporation of ananalyte insensitive channel b, the background signal may be incorporatedinto the equation above: y=m_(G)[G]+b. Incorporating the measurementsfrom a temperature sensor, the electrical current characteristic can berepresented by the following relation: y=m_(G)[G]+m_(T)[T]+b where m_(T)is the temperature sensitivity (e.g., pA/° C.), T is the measuredtemperature, and b is the background signal (e.g., pA). In otheroperating scenarios, the electrical current characteristic is modeled bythe following relation: y=m₁[G][T]+b where m₁ is a weighting factordetermined a priori. In other operating scenarios, the electricalcurrent characteristic can be modeled as a convolution of temperatureand glucose: y={m_(T)[T]+m₂}[G]+b where m₂ is a weighting factordetermined a priori. In yet other operating scenarios, the electricalcurrent characteristic is provided by the following relation:y={m_(G)[G]+m₂}[T][G]+b. In yet other operating scenarios, theelectrical current characteristic is given by the following nonlinearrelation: y={m_(G2)[G]²+m_(G)[G]}[T]+b where m_(G2) is a nonlinearweighting factor. In yet other operating scenarios, the electricalcurrent characteristic is given by the following Gaussian relation:y=m_(G)[G]exp{−([T]−[T_(OPT)])²/(2σ²)}+b where T_(OPT) is the optimaltemperature for maximal catalytic turnover of the enzyme and G is theoperating temperature range of the enzyme.

In some variations, the analyte monitoring device may include at leastone microneedle with an electrode configured to function as an analyteinsensitive channel (e.g., glucose insensitive channel) having a knowntemperature sensitivity, where such a known temperature sensitivity maybe used to compensate for temperature. For example, one advantage ofusing a glucose insensitive channel includes proximity to the glucosesensor (e.g., resulting in less error from thermal gradients) and cost(e.g., by reducing external components and specialized processes tothermally couple the sensor to the skin). In some variations, theanalyte monitoring device may include both an analyte insensitivechannel along with a thermistor, with an algorithm that utilizesinformation from both. Additionally or alternatively, the analytemonitoring device may include an additional sensor(s) that measuresambient temperature, which may also be useful in the temperaturecompensation algorithm.

In some variations, the analyte insensitive channel may be used toperform differential measurements and/or subtract background noiselevels from the analyte-sensitive channel(s) to improve signal fidelityand/or signal-to-noise ratio. The analyte insensitive channel may besensitive to common mode signals that also arise on theanalyte-sensitive channel(s) (e.g., endogenous and pharmacologicinterference, pressure attenuations, etc.).

Additionally or alternatively, in some variations, the analytemonitoring device may include at least one kinetic sensor. The kineticsensor may, for example, comprise an accelerometer, gyroscope, and/orinertial measurement unit to capture positional, displacement,trajectory, velocity, acceleration, and/or device orientation values.For example, such measurements may be used to infer the wearer'sphysical activity (e.g., steps, intense exercise) over a finiteduration. Additionally or alternatively, in some variations, the kineticsensor(s) may be employed to enable detection of wearer interactionswith the analyte monitoring device such as touch or tapping. Forexample, touch or tap detection can be employed to silence or snoozenotifications, alerts, and alarms, control a wirelessly connected mobilecomputing device, or to activate/deactivate a user interface on theanalyte monitoring device (e.g., an embedded display or indicatorlight). Touching or tapping may be performed in a defined sequenceand/or for a predetermined duration (e.g., at least 3 seconds, at least5 seconds) to elicit certain actions (e.g., display or indicator lightdeactivation/activation). Additionally or alternatively, in somevariations, the analyte monitoring device may enter into a power savingmode upon detection of limited motion or activity (e.g., absence ofsignificant acceleration) for at least a predetermined period of time(e.g., 15 minutes, 30 minutes, 45 minutes, 1 hour, or other suitable oftime), as measured by the kinetic sensor(s).

Additionally, or alternatively, in some variations, the analytemonitoring device may include at least one real-time clock (RTC). Thereal-time clock may be employed to track absolute time (e.g.,Coordinated Universal Time, UTC, or local time) when the analytemonitoring device is in storage or during use. In some variations,synchronization to absolute time may be performed followingmanufacturing of the analyte monitoring device. The real-time clock maybe employed to time-stamp analyte measurements (e.g., glucosemeasurements) during operation of the analyte monitoring device in orderto create a time-series data set that is communicated to a connectedperipheral device (e.g., mobile computing device), cloud storage, orother suitable data storage device, such as for later review by the user(e.g., wearer of the analyte monitoring device), their support network,or their healthcare provider, etc.

Power Source(s)

As shown in FIG. 2A, the analyte monitoring device may include one ormore power sources 130 (e.g., battery) in the housing 112 configured toprovide power to other components. For example, the analyte monitoringdevice may include an AgO battery, which has a high energy density andis more environmentally friendly than lithium batteries. In somevariations, a primary (e.g., non-rechargeable) battery may be used.Furthermore, in some variations, a secondary (e.g., rechargeable)battery may be used. However, any suitable power source may be used,including a lithium-based battery.

In some variations, the power source may be coupled to the device PCBusing a low profile holder or mount that reduces the overall height ofthe electronics, thereby minimizing the height or profile of the analytemonitoring device. For example, whereas traditional battery holdersapply force to the topside of the battery using a conductive metal witha spring force, in some variations a lateral mounted battery holder maycontact the sides of the battery to complete the electrical circuit. Forexample, as shown in FIG. 20 , a lateral mounted battery holder 2020 mayinclude an arcuate clip that clamps or otherwise contacts the sides ofthe battery without increasing vertical bulk. The battery holder 2020may further include one or more mounting holes to couple to the devicePCB via one or more suitable fasteners (and/or may couple to the devicePCB in any suitable manner). In some variations, the housing may besized and/or shaped with suitable tolerances so as to apply vertical ordownward force on the battery toward the device PCB, in order to keepthe battery in contact with the PCB.

Applicator

In some variations, the analyte monitoring device may be appliedmanually. For example, a user may remove a protective film on theadhesive layer, and manually press the device onto his or her skin on adesired wear site. Additionally or alternatively, as illustrated in FIG.1 , in some variations the analyte monitoring device may be applied tothe skin using a suitable applicator 160. The applicator 160 may, forexample, be configured to urge the analyte monitoring device 110 towardthe skin of the user such that the microneedle array 140 of the analytemonitoring device 110 may be inserted into the skin (e.g., to thedesired target depth).

Kits

In some variations, some or all components of the analyte monitoringsystem may be provided in a kit (e.g., to a user, to a clinician, etc.).For example, a kit may include at least one analyte monitoring device110 and/or at least one applicator 160. In some variations, a kit mayinclude multiple analyte monitoring devices 110, which may form a supplyof analyte monitoring devices sufficient that is for a predeterminedperiod of time (e.g., a week, two weeks, three weeks, a month, twomonths, three months, six months, a year, etc.). The kit may include anysuitable ratio of applicators to analyte monitoring devices (e.g., 1:1,lower than 1:1, greater than 1:1). For example, the kit may include thesame number of applicators as analyte monitoring devices, such as ifeach applicator is single-use and is configured to be disposed after itsuse in applying a respective analyte monitoring device to the user. Asanother example, the kit may include a number of applicators that islower than the number of analyte monitoring devices in the kit (e.g.,one applicator per two or three analyte monitoring devices), such as ifan applicator is intended to be reused for applying multiple analytemonitoring devices or if multiple analyte monitoring devices are loadedinto a single applicator for repeated applications. As another example,the kit may include a number of applicators that is higher than thenumber of analyte monitoring devices in the kit (e.g., two applicatorsper analyte monitoring device), such as to provide extra or redundantapplicators in case of applicator loss or breakage, etc.

In some variations, the kit may further include user instructions foroperating the analyte monitoring device and/or applicator (e.g.,instructions for applying the analyte monitoring device manually or withthe applicator, instructions for pairing the analyte monitoring devicewith one or more peripheral devices (e.g., computing devices such as amobile phone), etc.).

Sterilization of Analyte Monitoring Device

As described above, the analyte monitoring devices 110 such as thosedescribed herein are differentiated from other CGM devices at least inthat the sensing elements (e.g., microneedle array) and electronics areintegrated into one unit. One benefit to this integration is that theuser is not required to perform any assembly of the analyte monitoringdevice 110. However, there are sterilization-related challenges toenabling such integration

Traditional CGM devices and similar electrochemical sensors aretypically sterilized through processes that are incompatible withelectronics. For example, conventional electrochemical sensorsterilization use gamma radiation or electron beam radiation tosterilize the sensing elements. However, the bosonic or fermionicparticles associated with these sterilization processes interfere withelectronics operation. Thus, typically the electronic component(s) musteither be sterilized separately and require the end user to perform someassembly of the device, or the electronic component(s) are simply notsterilized, which may lead to contamination issues.

In contrast, the sensor technologies described above are configured tobe compatible with a form of sterilization that is suitable for both thesensing elements and the electronics. In some variations, as describedabove, the working electrodes in the microneedle array may include abiorecognition layer including a cross-linked biorecognition element.For example, the biorecognition element may be cross-linked with anamine-condensing carbonyl chemical species, which helps to bridge aminegroups and thus help stabilize the biorecognition element within thebiorecognition layer. For example, the biorecognition element mayinclude an enzyme (e.g., glucose oxidase) that is cross-linked withglutaraldehyde, formaldehyde, glyoxal, malonaldehyde, succinaldehyde,and/or other suitable species and then embedded in a conducting polymeras described above.

A result of the above-described cross-linked structure is that theenzyme is sufficiently stabilized so that it may undergo gaseous methodsof sterilization, such as ethylene oxide (EO) sterilization, withsurprisingly only minimal impact on sensing elements in terms of sensingperformance. Thus, since electronics may undergo EO sterilization, insome variations the analyte monitoring devices 110 are uniquely andadvantageously configured to survive an “all in one” sterilizationprocedure with their electronics and sensing elements fully integratedand simultaneously sterilized in a single unit, without damaging eitherset of components.

Accordingly, in some variations, a method of sterilizing an analytemonitoring device may include exposing the analyte monitoring device toa sterilant gas, where the analyte monitoring device includes a housing(e.g., wearable housing), a microneedle array extending from the housingand including an analyte sensor, and an electronics system arranged inthe housing and electrically coupled to the microneedle array. Theanalyte monitoring device is exposed to the sterilant gas for a dwelltime sufficient to sterilize the analyte monitoring device. In somevariations, the analyte monitoring device may be sterilized to aSterility Assurance Level (SAL) of 10⁻⁶ (i.e., having a probability thatnot more than 1 viable microorganism among 1,000,000 sterilizeddevices).

FIG. 21 illustrates an example variation of a method 2100 forsterilizing an analyte monitoring device. Method 2100 may include, forexample, inserting an analyte monitoring device into a chamber 2110suitable for sterilization, preconditioning the analyte monitoringdevice 2120, exposing the analyte monitoring device to a sterilant gas2130, and aerating the analyte monitoring device 2140.

FIG. 22 depicts a schematic of an example variation of a sterilizationsystem including a chamber (or series of chambers) suitable for use insterilizing an analyte monitoring device. For example, the sterilizationsystem may include at least one chamber for executing a preconditioningprocess, at least one chamber for a sterilizing process, and/or at leastone chamber for an aerating process. In some variations, the samechamber may be utilized for two or more these processes of method 2100.

Thus, for example, an analyte monitoring device may be placed within apreconditioning chamber for the preconditioning process 2120. Asdescribed above, the analyte monitoring device may be placed in thechamber as an integrated device, including both electrochemical sensingelements and electronic components.

Preconditioning may function to heat and humidify the analyte monitoringdevice to a stable temperature and moisture content prior to enteringthe sterilization chamber, which may help ensure consistency andreliability of the sterilization process, regardless of environmentalconditions. As shown in FIG. 23 , preconditioning the analyte monitoringdevice may include reducing the pressure in the chamber to a vacuum setpoint (e.g., 1.0 psia). The vacuum may be established gradually, such asat a rate of about 2 psia/minute or other suitable rate. Furthermore,preconditioning may include setting other environmental conditions tovarious set points for a predetermined dwell time. For example, as shownin FIG. 23 , after reducing the pressure to the vacuum set point, steammay be injected into the chamber so as to establish the temperature,relative humidity, and/or humidity at predetermined set points. Forexample in one implementation, temperature inside the chamber may be setto between about 35 degrees Celsius to about 40 degrees Celsius, orabout 38 degrees Celsius, which may be suitable so as to avoiddenaturing the biorecognition element (e.g., enzyme) from higher heatduring preconditioning. As another example, relative humidity may be setto between about 45% to about 55% (or about 51%). The temperature,relative humidity, and vacuum set points may be maintained for apredetermined dwell time, such as between about 90 minutes and about 180minutes, between about 100 minutes and about 100 minutes and about 160minutes, between about 110 minutes and about 140 minutes, or about 120minutes, or other suitable period of time. After the dwell time haspassed, the chamber may be evacuated and/or the conditioned analytemonitoring device may be removed and placed in a sterilization chamber.

As shown in FIG. 21 , after preconditioning the analyte monitoringdevice, the method may include exposing the analyte monitoring device toa sterilant gas 2130, such as ethylene oxide (EO). In some variations,the EO may be introduced into the sterilization chamber at a gasconcentration of between about 425 mg/L and about 475 mg/L, or about 450mg/L. As shown in FIG. 23 , during the sterilization process thepressure in the chamber may be set to a sterilant set point of betweenabout 5 psia and about 6 psia, or about 5.3 psia. In some variations, atleast about 97% of the air must be evacuated from the chamber prior todelivering EO gas into the chamber. Additionally or alternatively, aseries of partial vacuums may be established in the chamber followed bya series of nitrogen (N₂) injections to purge a sufficient amount of airfrom the chamber. Similar to the temperature during preconditioning,temperature of the chamber during sterilization may be set to betweenabout 35 degrees Celsius to about 40 degrees Celsius, or about 38degrees Celsius. Temperature may be increased to the temperature setpoint as EO is introduced. After introducing EO gas into the chamber,the analyte monitoring device may remain exposed to the EO gas for asuitable sterilant dwell time or exposure time. Suitable sterilant dwelltimes may, for example, range between about 90 minutes and about 180minutes, between about 100 minutes and about 100 minutes and about 160minutes, between about 110 minutes and about 140 minutes, or about 120minutes, or other suitable period of time sufficient for sterilizing theanalyte monitoring device. It should be understood that in somevariations, an increase in temperature during EO exposure will reducethe necessary EO dwell time (e.g., as a rule of thumb every 10 degreesCelsius increase in temperature may reduce the EO dwell time by abouthalf). Following the sterilant dwell time, the chamber may undergo avacuum/air cycle to purge the EO from the chamber.

As shown in FIG. 21 , the method 2100 may include aerating the analytemonitoring device 2140. Aeration of the analyte monitoring device mayallow for the additional removal of any residual gases from the device(e.g., prior to packaging and storage), as EO is flammable and anyresidual EO on the device post-sterilization can be extremely toxic. Insome variations, aeration may occur at room temperature. As shown inFIG. 23 , the aeration may last for a predetermined period of timesufficient to permit thorough outgassing. For example, the aerationprocess may last between at least about 4 hours and 24 hours, such asabout 12 hours. In other variations, the aeration process may last atleast about 12 hours, at least about 15 hours, or at least 24 hours,etc.

EXAMPLE

An EO sterilization cycle was evaluated for feasibility to sterilize ananalyte monitoring device such as those described herein. Briefly, thepreconditioning was done for two hours at a temperature of 38 degreesCelsius. This was followed by exposure to EO gas for two hours at 38degrees Celsius. After EO exposure, the samples were aerated to vent outthe EO gas at ambient temperatures for a minimum of 12 hours. Details ofthe EO exposure protocol are shown in Table 1:

TABLE 1 Example EO Exposure Protocol Sterilization Set Points EO GasConcentration 450 mg/L (100% EO) Temperature 38° C. Relative Humidity51% Initial Vacuum 1.0 psia EO Gas Dwell Time 120 minutes Steam DwellTime 120 minutes Aeration Set Points Temperature Ambient Time 12 hours(minimum) Post-Vacuum 3.5 psia DETOX A Initial Steam Flush 3.7 psiaInitial Steam Flush Dwell Time 0 min Steam Pulse 3.7 psia Steam PulseDwell Time 5 min Vacuum 3.5 psia Steam Flush 3.7 psia Steam Flush DwellTime 0 DETOX B Steam Pulse 3.7 psia Steam Pulse Dwell Time 5 minutesVacuum 3.5 psia Steam Flush 3.7 psia Steam Flush Dwell Time 0 min AirWashes 11.0-2.0 psia (5 total)

To test the stability of sensing chemistry following exposure to EO, sixfunctionalized microneedle sensors were subject to an EO sterilizationcycle. In this example, sensor chemistry using amide cross-linking ofglucose oxidase was evaluated in this feasibility study. FIG. 24 showsthe retained sensitivity for the six sensors after exposure to EO (EO),as well as for three sensors functioning as a negative control (do notprocess (DNP)). Overall, all six sensors that were exposed to EOremained sensitive to glucose post processing. The average percentagesensitivity retained was 75%.

Three of the sensors that were exposed to EO were also subsequentlytested for operational stability in PBS with 6 mM glucose over sevendays. Sensors were kept in solution and sensitivity was measured bycalibrating the sensors once per day. The summary results from theoperational stability testing are shown in FIG. 24B. It is seen that thesensors remained stable over the course of the test. No data wasobtained for days five and six due to instrument error. This trend issimilar to that observed for sensors sterilized with gamma irradiation.

Additionally, three sensors exposed to EO were used to test the storagestability. FIG. 24C shows the average sensitivity on Day 0 (Pre EOexposure), Day 14, and Day 28. The sensors were stored dry between day14 and 28 at 37 degrees C. The average sensitivity retained from Day 14to Day 28 of dry storage was 92%. This shows the potential to be able tosterilize using EO and store the sensors after exposure to EO.

Thus, the cross-linked sensor chemistry was found to be sufficientlystable to EO exposure, indicating that using EO process is feasible tosterilize an analyte monitoring device with sensing elements includingthe cross-linked sensor chemistry. Additionally, the chemistry after EOexposure was stable over seven days of active operation and also duringdry storage.

In some variations, the sensor may be decoupled from the electronics andundergo other suitable methods of sterilization, including those basedon irradiation by means of gamma rays/particles or with an electron beamof sufficient acceleration potential. Dosage of sterilization (e.g.,duration and particle energy) may be controlled in to achieve asatisfactory level of sterility, including a sterility assurance level(SAL) of less than 1E-6. In some variations, the electronics do notrequire sterilization as they do not contact breached or compromisedskin surfaces. In such variations, the electronics may be coupled to thesensor prior to the application of the entire system to the user's skin.

Use of Analyte Monitoring System

Described below is an overview of various aspects of a method of use andoperation of the analyte monitoring system, including the analytemonitoring device and peripheral devices, etc.

Application of Analyte Monitoring Device

As described above, the analyte monitoring device is applied to the skinof a user such that the microneedle array in the device penetrates theskin and the microneedle array's electrodes are positioned in the upperdermis for access to dermal interstitial fluid. For example, in somevariations, the microneedle array may be geometrically configured topenetrate the outer layer of the skin, the stratum corneum, bore throughthe epidermis, and come to rest within the papillary or upper reticulardermis. The sensing region, confined to the electrode at the distalextent of each microneedle constituent of the array (as described above)may be configured to rest and remain seated in the papillary or upperreticular dermis following application in order to ensure adequateexposure to circulating dermal interstitial fluid (ISF) without the riskof bleeding or undue influence with nerve endings.

In some variations, the analyte monitoring device may include a wearablehousing or patch with an adhesive layer configured to adhere to the skinand fix the microneedle array in position. While the analyte monitoringdevice may be applied manually (e.g., removing a protective film on theadhesive layer, and manually pressing the patch onto the skin on adesired wear site), in some variations the analyte monitoring device maybe applied to the skin using a suitable applicator.

The analyte monitoring device may be applied in any suitable location,though in some variations it may be desirable to avoid anatomical areasof thick or calloused skin (e.g., palmar and plantar regions), or areasundergoing significant flexion (e.g., olecranon or patella). Suitablewear sites may include, for example, on the arm (e.g., upper arm, lowerarm), shoulder (e.g., over the deltoid), back of hands, neck, face,scalp, torso (e.g., on the back such as in the thoracic region, lumbarregion, sacral region, etc. or on the chest or abdomen), buttocks, legs(e.g., upper legs, lower legs, etc.), and/or top of feet, etc.

As described above, in some variations the analyte monitoring device maybe configured to automatically activate upon insertion, and/or confirmcorrect insertion into skin. Details of these features are described infurther detail above. In some variations, methods for performing suchactivation and/or confirmation may be similar to that described in U.S.patent application Ser. No. 16/051,398, which was incorporated byreference above.

Pairing to Peripheral Device

In some variations, the analyte monitoring device may be paired to atleast one peripheral device such that the peripheral device receivesbroadcasted or otherwise transmitted data from the analyte monitoringdevice, including measurement data. Suitable peripheral devices include,for example a mobile computing device (e.g., smartphone, smartwatch)which may be executing a mobile application.

Additionally alternatively, an analyte monitoring device may be paired(or otherwise combined) with a therapeutic delivery device (e.g.,insulin pen or pump). For example, an analyte monitoring device may becombined with a therapeutic delivery device in a manner similar to thatdescribed in U.S. Patent App. Nos. 62/823,628 and 62/862,658, each ofwhich is incorporated herein in its entirety by this reference. Studieshave shown that users with insulin delivery devices that have smartalgorithms controlling dosing are in euglycemic range (i.e. healthyblood glucose levels)>95% of the time when CGM is available. The abilityof the analyte monitoring device to communicate directly with insulindelivery devices (i.e. no intermediary smartphone required) allows usersto achieve increased time in range significantly by eliminating the timewhen CGM is not available (during warmup or swap in of analytemonitoring devices). This feature may also enable users to wear multipleanalyte monitoring devices that detect different analytes simultaneouslyand input data into the same mobile application.

As described above, the pairing may be accomplished through suitablewireless communication modules (e.g., implementing Bluetooth). In somevariations, the pairing may occur after the analyte monitoring device isapplied and inserted into the skin of a user (e.g., after the analytemonitoring device is activated). Additionally or alternatively, thepairing may occur prior to the analyte monitoring device being appliedand inserted into the skin of a user.

Thus, the paired mobile or other device may receive the broadcasted ortransmitted data from the analyte monitoring device. The peripheraldevice may display, store, and/or transmit the measurement data to theuser and/or healthcare provider and/or support network. Furthermore, insome variations, the said paired mobile or wearable device performsalgorithmic treatment to the data to improve the signal fidelity,accuracy, and/or calibration, etc. In some variations, measurement dataand/or other user info may additionally or alternatively be communicatedand/or stored via network (e.g., cloud network).

By way of illustration, in some variations a mobile computing device orother computing device (e.g., smartphones, smartwatches, tablets, etc.)may be configured to execute a mobile application that provides aninterface to display estimated glucose values, trend information andhistorical data, etc. Although the below description refers specificallyto glucose as a target analyte, it should be understood that thefeatures and processes described below with respect to glucose may besimilarly applied to applications relating to other kinds of analytes.

In some variations, the mobile application may use the mobile computingdevice's Bluetooth framework to scan for the analyte monitoring device.As shown in FIG. 26 , the analyte monitoring device may power on orinitialize as soon as it is applied to the skin, and the analytemonitoring device may begin the advertising process. The mobileapplication may then connect to the analyte monitoring device and beginpriming the sensor for measurement. In case the mobile applicationdetects multiple analyte monitoring devices, the mobile application maydetect the analyte monitoring device that is closest in proximity toitself and/or may request the user (e.g., via the user interface on themobile device) to confirm disambiguation. In some variations, the mobileapplication may also be capable of connecting to multiple analytemonitoring devices simultaneously. This may be useful, for example, toreplace sensors that are reaching the end of their lifetime.

In some variations, the Bluetooth® Low Energy™ (BLE) protocol may beused for connectivity. For example, the sensor implements a custom BLEperipheral profile for the analyte monitoring system. Data may beexchanged after establishing a standard secure BLE connection betweenthe analyte monitoring device and the smartphone, smartwatch, or tabletrunning the mobile application. The BLE connection may be maintainedpermanently for the life of the sensor. If the connection is broken dueto any reasons (e.g., weak signal) the analyte monitoring device maystart advertising itself again and the mobile application mayre-establish the connection at the earliest opportunity (i.e. when inrange/physical proximity).

In some variations, there may be one or more additional layers ofsecurity implemented on top of the BLE connection to ensure authorizedaccess consisting of a combination of one or more techniques such aspasscode-protection, shared-secrets, encryption and multi-factorauthentication.

The mobile application may guide the user through initiating a newanalyte monitoring device. Once this process completes, the mobileapplication is not be required for the analyte monitoring device tooperate and record measurements. In some variations, a smart insulindelivery device that is connected to the analyte monitoring device canbe authorized from the mobile application to receive glucose readingsfrom the sensor directly. Additionally or alternatively, a secondarydisplay device like a smartwatch can be authorized from the mobileapplication to receive glucose readings from the sensor directly.

Furthermore, in some variations the mobile application may additionallyor alternatively help calibrate the analyte monitoring device. Forexample, the analyte monitoring device may indicate a request forcalibration to the mobile application, and the mobile application mayrequest calibration input from the user to calibrate the sensor.

Sensor Measurements

Once the analyte monitoring device is inserted and warm-up and anycalibration has completed, the analyte monitoring device may be readyfor providing sensor measurements of a target analyte. The targetanalyte (and any requisite co-factor(s)) diffuses from the biologicalmilieu, through the biocompatible and diffusion-limiting layers on theworking electrode, and to the biorecognition layer including thebiorecognition element. In the presence of a co-factor (if present), thebiorecognition element may convert the target analyte to anelectroactive product.

A bias potential may be applied between the working and referenceelectrodes of the analyte monitoring device, and an electrical currentmay flow from the counter electrode to maintain the fixed potentialrelationship between the working and reference electrodes. This causesthe oxidation or reduction of the electroactive product, causing acurrent to flow between the working electrodes and counter electrodes.The current value is proportional to the rate of the redox reaction atthe working electrode and, specifically, to the concentration of theanalyte of interest according to the Cottrell relation as described infurther detail above.

The electrical current may be converted to a voltage signal by atransimpedance amplifier and quantized to a digital bitstream by meansof an analog-to-digital converter (ADC). Alternatively, the electricalcurrent may be directly quantized to a digital bitstream by means of acurrent-mode ADC. The digital representation of the electrical currentmay be processed in the embedded microcontroller(s) in the analytemonitoring device and relayed to the wireless communication module forbroadcast or transmission (e.g., to one or more peripheral devices). Insome variations, the microcontroller may perform additional algorithmictreatment to the data to improve the signal fidelity, accuracy, and/orcalibration, etc.

In some variations, the digital representation of the electricalcurrent, or sensor signal, may be correlated to an analyte measurement(e.g., glucose measurement) by the analyte monitoring device. Forexample, the microcontroller may execute a programmed routine infirmware to interpret the digital signal and perform any relevantalgorithms and/or other analysis. Keeping the analysis on-board theanalyte monitoring device may, for example, enable the analytemonitoring device to broadcast analyte measurement(s) to multipledevices in parallel, while ensuring that each connected device has thesame information. Thus, generally, the user's target analyte (e.g.,glucose) values may be estimated and stored in the analyte monitoringdevice and communicated to one or more peripheral devices.

Data exchange can be initiated by either the mobile application or bythe analyte monitoring device. For example, the analyte monitoringdevice may notify the mobile application of new analyte data as itbecomes available. The frequency of updates may vary, for example,between about 5 seconds and about 5 minutes, and may depend on the typeof data. Additionally or alternatively, the mobile application mayrequest data from the analyte monitoring device (e.g., if the mobileapplication identifies gaps in the data it has collected, such as due todisconnections).

If the mobile application is not connected to the analyte monitoringdevice, the mobile application may not receive data from the sensorelectronics. However, the electronics in the analyte monitoring devicemay store each actual and/or estimated analyte data point. When themobile application is reconnected to the analyte monitoring device, itmay request data that it has missed during the period of disconnectionand the electronics on the analyte monitoring device may transmit thatset of data as well (e.g., backfill).

Generally, the mobile application may be configured to provide displayof real-time or near real-time analyte measurement data, such as on thedisplay of the mobile computing device executing the mobile application.In some variations, the mobile application may communicate through auser interface regarding analysis of the analyte measurement, such asalerts, alarms, insights on trends, etc. such as to notify the user ofanalyte measurements requiring attention or follow-up action (e.g., highanalyte values, low analyte values, high rates of change, analyte valuesoutside of a pre-set range, etc.). In some variations, the mobileapplication may additionally or alternatively facilitate communicationof the measurement data to the cloud for storage and/or archive forlater retrieval.

Interpreting Analyte Monitoring Device User Interface

In some variations, information relating to analyte measurement dataand/or the analyte monitoring device may be communicated via a userinterface of the analyte monitoring device. In some variations, the userinterface of the analyte monitoring device may be used to communicateinformation to a user in addition to, or as an alternative to,communicating such information via a peripheral device such as through amobile application on a computing device. Accordingly, a user and/orthose around the user may easily and intuitively view the analytemonitoring device itself for an assessment of analyte measurement data(e.g., analyte measurement status such as current and/or trendinganalyte measurement levels) and/or device status, without the need toview a separate device (e.g., peripheral device or other device remotefrom, and in communication with, the analyte monitoring device).Availability of such information directly on the analyte monitoringdevice itself may also enable a user and/or those around the user tomore promptly be alerted of any concerns (e.g., analyte measurementsthat are above or below target range, and/or analyte measurements thatare increasing or decreasing at an alarming rate), thereby enabling auser to take appropriate corrective action more quickly.

For example, FIGS. 32A-32C depict an example variation of an analytemeasurement device 3200 including a user interface 3220 with multipleindicator lights, including indicator lights 3224 a-3224 c, which may beselectively illuminated to communicate a user status (e.g., informationrelating to analyte measurement in the user). The user interface 3220may be similar, for example, to user interface 3120 described above withrespect to FIG. 31A and/or FIG. 31B. Although the user interface 3220includes three indicator lights 3224 a-3224 c, it should be understoodthat in some variations, the user interface 3220 may include anysuitable number of lights, including fewer than three (e.g., one, two)or more than three (e.g., four, five, six, or more).

The indicator lights 3224 a-3224 c may be arranged in a sequentialmanner such that their relative positions help a user to intuitivelyunderstand information communicated collectively by the user interface.For example, the three indicator lights 3224 a-3224 c may be illuminatedto generally indicate three progressive levels (or ranges) of analytemeasurements: the lowest indicator light 3224 a may be illuminated togenerally indicate an analyte measurement that is lowest of the threelevels, the middle indicator light 3224 b may be illuminated togenerally indicate an analyte measurement that is in the middle of thethree levels, and the highest indicator light 3224 c may be illuminatedto generally indicate an analyte measurement that is highest of thethree levels. In one example variation, the lowest indicator light 3224a may be illuminated to indicate an analyte measurement that is in atarget range (FIG. 32A), the middle indicator light 3224 b may beilluminated to indicate an analyte measurement that is above a targetrange (FIG. 32B), and the highest indicator light 3224 c may beilluminated to indicate an analyte measurement that is significantlyabove a target range (FIG. 32C). In another example variation, thelowest indicator light 3224 a may be illuminated to indicate an analytemeasurement that is below a target range, the middle indicator light3224 b may be illuminated to indicate an analyte measurement that iswithin the target range, and the highest indicator light 3224 c may beilluminated to indicate an analyte measurement that is above a targetrange.

The threshold values for a target range may be any suitable values. Forexample, in some variations in which glucose monitoring is beingperformed, analyte measurements may be considered within a target rangeif they are between about 70 mg/dL and about 180 mg/dL (or between about80 mg/dL or about 60 mg/dL and about 170 mg/dL or about 190 mg/dL,etc.), and may be considered below a target range if they are belowabout 70 mg/dL (or below about 80 mg/dL, or below about 60 mg/dL, etc.).The different thresholds for “above” a target range and “significantly”above a target range may have any suitable value. For example, in somevariations, analyte measurements may be considered “above” a targetrange if it is above a first predetermined threshold (e.g., above athreshold value of about 180 mg/dL for hyperglycemia determination inglucose monitoring, or above a threshold value that is between about 170mg/dL and about 200 mg/dL for hyperglycemia determination in glucosemonitoring) and analyte measurement may be considered “significantlyabove” a target range if it is a predetermined amount (e.g., percentage)above the first predetermined threshold, such as at least 33% above thefirst predetermined threshold (e.g., >240 mg/dL for extremehyperglycemia determination in glucose monitoring), or at least about25% above the first predetermined threshold, at least about 30% abovethe first predetermined threshold, at least 35% above the firstpredetermined threshold, or at least 40% above the first predeterminedthreshold, or other suitable second predetermined threshold.

Furthermore, the thresholds for considering analyte measurements withintarget range, or below target range, or “above” target range or“significantly above” target range (or other characterization of theanalyte measurements) may be static or dynamic, and/or may vary based onuser information such as historical measurements and/or trends or otherhistorical data (e.g., relative to an average or expected analytemeasurement for the user at particular times or average or expected rateof change). Furthermore, it should be understood that while the userinterface 3220 includes three sequential indicator lights, in othervariations a user interface on the housing of an analyte monitoringdevice may include fewer (e.g., two) or more (e.g., four, five, six, ormore) that may be similarly illuminated individually to indicate ananalyte measurement (e.g., each corresponding to a general relativelevel of analyte measurement).

In some variations, different illumination colors and/or timing for oneor more of the indicator lights 3224 a-3224 c may additionally oralternatively enable a user to easily distinguish between each analytemeasurement level. For example, when an analyte measurement is within atarget range, the appropriate indicator light(s) may be illuminated in afirst color (e.g., blue), while when the analyte measurement is outsidethe target range, the appropriate indicator light(s) may be illuminatedin another color (e.g., white for below target range, orange for abovetarget range). As another example, when the analyte measurement iswithin a target range, the appropriate indicator light(s) may beilluminated in a first temporal pattern (e.g., long, gentle pulse ofillumination “on” time), while when the analyte measurement is outsidethe target range, the appropriate indicator light(s) may be illuminatedin another temporal pattern (e.g., short, flash-like pulse ofillumination “on” time). Shorter pulses of illumination “on” time may,for example, be helpful to better attract user attention and/or moreintuitively communicate an alert when the analyte measurement is below atarget range, above a target range, or significantly above a targetrange. Higher frequency illumination may, in some variations, correlateto greater alert level (e.g., significantly below the target range orsignificantly above the target range).

FIGS. 33A-33D and Table 2 illustrate different illuminating modes usedin an example method of operating the user interface 3220 of an analytemonitoring device. The exact parameter values of these illuminationmodes are non-limiting and are included for an example variation forillustrative purposes only. For example, in the “below target range”illumination mode, the illumination color may be any suitable color,and/or the illumination “on” time may be between about 0.1 seconds and 1second, between about 0.2 seconds and 0.5 seconds, or about 0.3 seconds,and/or the illumination “off” time may be between about 0.5 seconds andabout 5 seconds, or between about 1 second and about 4 seconds, orbetween about 2 seconds and about 4 seconds, or about 3 seconds; and/orthe ratio between the illumination “on” and illumination “off” times maybe about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, and/or othersuitable illumination parameters. As another example, in the “in targetrange” illumination mode and/or the “above target range illuminationmode, the illumination color may be any suitable color, and/or theillumination “on” time may be between about 0.1 seconds and about 3seconds, between about 0.5 seconds and about 2 seconds, or about 1second, and/or the illumination “off” mode may be between about 0.5seconds and about 5 seconds, or between about 1 second and about 4seconds, or between about 2 seconds and about 4 seconds, or about 3seconds, and/or the ratio between the illumination “on” and illumination“off” times may be about 0.1, about 0.2, about 0.3, about 0.4, about0.5, and/or other suitable illumination parameters. As another example,in the “significantly above target range”, the illumination color may beany suitable color, and/or the illumination “on” time may be betweenabout 0.2 seconds and 2 seconds, between about 0.5 seconds and about 1.5seconds, or about 0.8 seconds, and/or the illumination “off” time may bebetween about 0.5 seconds and about 5 seconds, or between about 1 secondand about 4 seconds, or between about 2 seconds and about 4 seconds, orabout 3 seconds and/or other suitable illumination parameters.Furthermore, fewer or more illumination modes for indicating analytemeasurement level may be possible in other variations.

TABLE 2 Example illumination modes for indicating analyte measurementAnalyte Indicator Illumination Illumination measurement lightIllumination “on” “off” level FIG. illuminated color time t(on) timet(off) Below target FIG. 33A Lowest White 0.3 sec 3 sec range In targetFIG. 33B Lowest Blue 1 sec 3 sec range Above target FIG. 33C MiddleOrange 1 sec 3 sec range Significantly FIG. 33D Highest Orange 0.8 sec 3sec above target range

Additionally or alternatively, in some variations, the indicator lights3224 a-3224 c may be illuminated in a progressive sequence to indicatetrend information of analyte measurements over time. For example, asshown in FIG. 34A, a progressive sequence of illumination of theindicator lights 3224 a-3224 c in a first direction from lower indicatorlight(s) to higher indicator light(s) (e.g., indicator light 3224 afollowed by indicator light 3244 b, followed by indicator light 3224 c)may intuitively indicate a trend of increasing analyte measurements. Insome variations, the progressive sequence of illumination could have anysuitable illumination color. In some variations, such rising sequentialillumination of indicator lights may be in a suitable color to indicateeither that the current analyte measurement is within a target range andrising, or that the current analyte measurement is above a target rangeand rising. For example, FIG. 34A illustrates rising progressiveillumination in a first color (e.g., blue) to indicate that currentanalyte measurement is within the target range and rising, whereas FIG.34B illustrates rising progressive illumination in a second color (e.g.,orange) to indicate that the current analyte measurement is above (orsignificantly above) the target range and rising. As yet anotherexample, a rising progressive illumination in a third color (e.g.,white) may indicate that the current analyte measurement is below (orsignificantly below) the target range and rising.

As another example, as shown in FIG. 34C, a progressive sequence ofillumination of the indicator lights 3224 a-3224 c in a second direction(e.g., opposite direction of the first direction) from higher indicatorlight(s) to lower indicator light(s) (e.g., indicator light 3224 cfollowed by indicator light 3244 b, followed by indicator light 3224 a)may intuitively indicate a trend of decreasing analyte measurements.Similar to that described above with respect to FIGS. 34A and 34B, sucha falling progressive sequence of illumination of indicator lights maybe a suitable color to indicate the status of the current analytemeasurement that is falling (e.g., falling progressive illumination in afirst color (e.g., blue) to indicate that current analyte measurement iswithin the target range and falling, falling progressive illumination ina second color (e.g., orange) to indicate the current analytemeasurement is above (or significantly above) the target range andfalling, or falling progressive illumination in a third color (e.g.,white) may indicate that the current analyte measurement is below (orsignificantly below) the target range and falling.

It should be understood that other variations of progressive sequencesof illumination may be used to similarly indicate analyte measurementtrends. For example, a 1-dimensional array of indicator lights (e.g.,arranged in a row, a column, an arc, etc.) may be illuminated in aprogressive sequence from a first end of the array to a second end ofthe array to indicate a rising analyte measurement trend, andilluminated in a progressive sequence from a second end of the array toa first end of the array to indicate a falling analyte measurementtrend. For example, progressive sequences of illumination may becharacterized as left-to-right, right-to-left, top-to-bottom,bottom-to-top, clockwise, counter-clockwise, etc. Furthermore, it shouldbe understood that while the user interface 3220 includes threesequential indicator lights, in other variations a user interface on thehousing of an analyte monitoring device may include fewer (e.g., two) ormore (e.g., four, five, six, or more) that may be similarly illuminatedin a progressive sequence to indicate rising and/or falling analytemeasurement trends.

In some variations, within each rising or falling sequence ofillumination across the indicator lights, the illumination of adjacentindicator lights may be interspersed by an illumination “off” period.Furthermore, in some variations, the pace at which the illuminationtransitions between indicator lights may indicate rate of change ofanalyte measurements. For example, the faster the illuminationtransitions from lower to higher indicator lights, the faster the rateof change (and potentially the greater urgency or need for userattention to the trend). Additionally or alternatively, each rising orfalling sequence of illumination across the indicator lights may beseparated by a sequence end illumination “off” time in order to helpdistinguish between a rising sequence and a falling sequence. Thesequence end illumination “off” time may be longer than the illumination“off” period within each sequence. In some variations, the start or endof each rising or falling sequence of illumination may additionally oralternatively be demarcated in any suitable manner (e.g., illuminatingall lights simultaneously at the start or end of a rising or fallingsequence).

Table 3 illustrates different illumination modes used in an examplemethod of operating the user interface 3220 of an analyte monitoringdevice to indicate analyte measurement trends. The exact parametervalues of these illumination modes are non-limiting and are included foran example variation for illustrative purposes only. For example, in aprogressive sequence of illumination (e.g., for any one of more suitableillumination modes), the illumination color may be any suitable color,and/or the illumination “on” time may be between about 0.1 seconds and 1second, between about 0.2 seconds and 0.5 seconds, or about 0.3 seconds,and/or the illumination “off” time between illumination of adjacentindicator lights may be between about 0.05 seconds and about 1 second,between about 0.1 seconds and about 0.5 seconds, or about 0.18 seconds,and/or the ratio between the illumination “on” time and illumination“off” time may be about 1, about 1.5, or about 2, and/or the sequenceend may be designated by illumination “off” for between about 2 secondsand about 5 seconds, or about 3 seconds. Furthermore, fewer or moreillumination modes for indicating analyte measurement trends may bepossible in other variations.

TABLE 3 Example illumination modes for indicating analyte measurementtrends Indicator Analyte lights Illumination Illumination measurementillumination Illumination “on” “off’ Sequence trend FIG. sequence colortime time end In target FIG. Lower → Blue 0.3 sec 0.18 sec 3 sec range,34A Higher illumination rising “off” Above FIG. Lower → Orange 0.3 sec0.18 sec 3 sec target 34B Higher illumination range, “off” rising AboveFIG. Higher → Orange 0.3 sec 0.18 sec 3 sec (and/or 34C Lowerillumination significantly “off” above) target range, dropping

Additionally or alternatively, an indicator light 3222 may beselectively illuminated to communicate a device status. Similar to thatdescribed above, color and/or timing of illumination may be varied in apredetermined manner to indicate different device statuses. Status may,for example, include a warm-up period notification, an end-of-lifenotification, a sensor fault state notification, a sensor failure mode(e.g., improper insertion) notification, a low battery notification,and/or a device error notification. Furthermore, any suitable number ofindicators lights may be illuminated individually and/or collectively(e.g., in sequence or simultaneously) to indicate different devicestatuses. For example, as shown in FIG. 35A, a user interface includingan indicator light 3222 may be illuminated in a first illumination mode(e.g., first illumination color such as white and/or first temporalillumination pattern) to indicate a device “wait” mode. The wait modemay, for example, correspond to a device warmup period (as describedelsewhere herein), detection of a temporary error (e.g., detection ofpressure-induced sensor attenuation). As another example, as shown inFIG. 35B, a user interface including an indicator light 3222 may beilluminated in a second illumination mode (e.g., second illuminationcolor such as red and/or second temporal illumination pattern) toindicate a device “end of life” mode (e.g., determination of an end of apredetermined wear period such as that described below, detection of apermanent error, etc.).

Table 4 illustrates different illumination modes used in an examplemethod of operating the user interface of an analyte monitoring deviceto indicate device status. The exact parameter values of theseillumination modes are non-limiting and are included for an examplevariation for illustrative purposes only. For example, in the “wait”illumination mode, the illumination color may be any suitable color,and/or the illumination “on” time may be between about 0.1 seconds andabout 3 seconds, between about 0.5 seconds and about 2 seconds, or about1 second, and/or the illumination “off” mode may be between about 0.5seconds and about 5 seconds, or between about 1 second and about 4seconds, or between about 2 seconds and about 4 seconds, or about 3seconds, and/or the ratio between the illumination “on” and illumination“off” times may be about 0.1, about 0.2, about 0.3, about 0.4, about0.5, and/or other suitable illumination parameters. As another example,in the “end of life” illumination mode, the illumination color may beany suitable color, and/or the illumination “on” time may be betweenabout 0.01 seconds and about 1 second, between about 0.01 seconds andabout 0.5 seconds, between about 0.01 seconds and about 0.3 seconds,between about 0.01 seconds and about 0.1 seconds, or about 0.04 seconds,and/or the illumination “off” time may be between about 1 second andabout 10 seconds, between about 3 seconds and about 8 seconds, or about6 seconds, and/or the ratio between the illumination “on” andillumination “off” times may be about 0.3, about 0.2, about 0.1, about0.05, about 0.01, or less than about 0.01, and/or other suitableillumination parameters. Although only two illumination modes are shown,in some variations an analyte monitoring device may have fewer or moreillumination modes, such as for each of the above statuses (e.g., firstillumination mode for a device warmup period, a second illumination modefor detection of a temporary error, a third illumination mode fordetermination of an end of device lifetime, a fourth illumination modefor detection of a permanent error, etc.).

TABLE 4 Example illumination modes for indicating device statusIllumination Illumination Device Illumination “on” “off” status FIG.color time t(on) time t(off) Wait FIG. 35A White 1 sec 3 sec End of lifeFIG. 35B Red 0.04 sec 6 sec

In some variations, a photodiode, phototransistor, photodetector, orother suitable ambient light sensor may be employed to measure theillumination level in the device's immediate environment. The ambientlight measurement may, for example, be used to trigger an adjustment(e.g., dimming) of the brightness of the user interface (e.g., display,indicator light(s), etc.) to conserve battery charge in a power savingmode, to improve contrast under various illumination scenarios, and/orto reduce device visibility to other individuals. For example, theanalyte monitoring device may enter the power saving mode in response tomeasurements from the ambient light sensor indicating general absence ofambient light (e.g., sufficient darkness for at least a predeterminedperiod of time) such as when the device is placed under the clothing ofa wearer or when the wearer is asleep in a dark environment. In thesescenarios, the power saving mode may be practical because the indicatorlights may have limited utility when concealed and out of view of thewearer (e.g., under clothing) or otherwise may be perceived as anannoyance (e.g., during slumber), etc. In response to measurements fromthe ambient light sensor indicating exposure to ambient light (e.g.,sufficient brightness for at least a predetermined period of time), theanalyte monitoring device may then exit the power saving mode andincrease the brightness of the user interface accordingly.

Additional System Functions

In some variations, the mobile application may help a user manage thelifetimes and replacement of analyte monitoring devices. For example,the mobile application may terminate data display when the wear periodof the analyte monitoring device has elapsed. In some variations, theanalyte monitoring device may have enhanced longevity compared toconventional CGM devices. For example, the analyte monitoring devicesdescribed herein may have a wear period (e.g., intended lifetime) of atleast 3 days, at least 5 days, at least 6 days, at least 7 days, atleast 10 days, or at least 12 days, between 5 days and between 10 days,between 10 days and 14 days, etc. without material loss in performance.

Additionally or alternatively, mobile application may provideconfigurable alerts to the user that the wear period is about to elapse,which permits users to apply a new analyte monitoring device when thecurrent analyte monitoring device is still active but close to expiry.Additionally, the new analyte monitoring device can warm up (typicallybetween about 30 minutes and about 2 hours) while the old unit is stilldelivering analyte measurements. The old analyte monitoring device canthen be removed upon expiry. The new analyte monitoring device may thenbecome the primary sensor delivering analyte measurements to the mobileapplication. This may provide for an uninterrupted coverage for analytemeasurements. Additionally, the readings from the old analyte monitoringdevice may be used to calibrate or algorithmically improve the accuracyof the new analyte monitoring device.

In some variations, an analyte monitoring device may have a uniqueserial number contained within the microcontroller (e.g., located in theelectronics system). This serial number may enable sensors to be trackedfrom manufacturing and throughout the use of the product. For example,sensor device history records including manufacturing and customer usemay be transmitted and stored in the cloud database. This enablestracking and inferences to be made on various parameters such as sensorperformance metrics and improvement for individual users as well assensor lots, tracking defective sensor lots back from field data tomanufacturing or supplier issues very rapidly, personalized healthmonitoring features for individual users, etc.

In some variations, the system may be able to track inventory of analytemonitoring devices from warehousing to purchasing transactions toproduct use, which may enable the system to assist users in fulfillmentof timely orders (e.g., to ensure that users don't run out of analytemonitoring devices). Additionally or alternatively, fulfillment can beexecuted automatically as monitoring device utilization is tracked, andtimely delivery can be made to the user's residence to help ensure thatsensor supply never depletes (e.g. ‘just-in-time’ delivery). This caninterface with virtual or e-pharmacies, logistics centers, and/orweb-based sales portals, such as Amazon™.

Through web portals, the cloud infrastructure may also allow users toview their real-time and historical glucose data/trends and share thesaid data with caregivers, their healthcare provider(s), supportnetwork, and/or other suitable persons.

ENUMERATED EMBODIMENTS

Embodiment I-1. A microneedle array for use in sensing an analyte,comprising:

-   -   a plurality of solid microneedles, wherein at least one        microneedle comprises:    -   a tapered distal portion having an insulated distal apex; and    -   an electrode on a surface of the tapered distal portion, wherein        the electrode is located proximal to the insulated distal apex.

Embodiment I-2. The microneedle array of embodiment I-1, wherein theelectrode is a working electrode configured to sense at least oneanalyte and the at least one microneedle comprises a biorecognitionlayer arranged over the working electrode, wherein the biorecognitionlayer comprises a biorecognition element.

Embodiment I-3. The microneedle array of embodiment I-2, wherein thebiorecognition element comprises an enzyme.

Embodiment I-4. The microneedle array of embodiment I-3, wherein theenzyme is an oxidoreductase.

Embodiment I-5. The microneedle array of embodiment I-4, wherein theoxidoreductase is at least one of lactate oxidase, alcohol oxidase,beta-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbateoxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, urateoxidase, urease, and xanthine oxidase.

Embodiment I-6. The microneedle array of embodiment I-4, wherein theoxidoreductase is glucose oxidase.

Embodiment I-7. The microneedle array of embodiment I-2, wherein thebiorecognition element is cross-linked with an amine-condensing carbonylchemical species.

Embodiment I-8. The microneedle array of embodiment I-7, wherein theamine-condensing carbonyl chemical species is at least one offormaldehyde, glyoxal, malonaldehyde, and succinaldehyde.

Embodiment I-9. The microneedle array of embodiment I-7, wherein theamine-condensing carbonyl chemical species is glutaraldehyde.

Embodiment I-10. The microneedle array of embodiment I-2, wherein the atleast one microneedle comprises at least one of a diffusion-limitinglayer and a hydrophilic layer arranged over the biorecognition layer.

Embodiment I-11. The microneedle array of embodiment I-2, wherein themicroneedle array comprises at least one microneedle comprising acounter electrode configured to source or sink current to sustain anelectrochemical reaction on the working electrode.

Embodiment I-12. The microneedle array of embodiment I-2, wherein themicroneedle array comprises at least one microneedle comprising areference electrode configured to provide a reference potential for theworking electrode.

Embodiment I-13. The microneedle array of embodiment I-12, furthercomprising a conducting polymer arranged over the reference electrode.

Embodiment I-14. The microneedle array of embodiment I-13, wherein theconducting polymer comprises a dopant.

Embodiment I-15. The microneedle array of embodiment I-13, wherein thereference electrode comprises a metal oxide with a stable electrodepotential.

Embodiment I-16. The microneedle array of embodiment I-15, wherein themetal oxide comprises iridium oxide.

Embodiment I-17. The microneedle array of embodiment I-13, wherein thereference electrode comprises a metal salt with a stable electrodepotential.

Embodiment I-18. The microneedle array of embodiment I-17, wherein themetal salt comprises silver chloride.

Embodiment I-19. The microneedle array of embodiment I-1, wherein theentirety of the electrode is on the tapered distal portion of the atleast one microneedle.

Embodiment I-20. The microneedle array of embodiment I-1, wherein theelectrode comprises a catalytic surface.

Embodiment I-21. The microneedle array of embodiment I-20, wherein thecatalytic surface comprises at least one of platinum, palladium,iridium, rhodium, gold, ruthenium, titanium, nickel, carbon, and dopeddiamond.

Embodiment I-22. The microneedle array of embodiment I-20, wherein theat least one microneedle comprises platinum black arranged over theelectrode.

Embodiment I-23. The microneedle array of embodiment I-1, wherein adistal end of the electrode is offset from the distal apex by an offsetdistance of at least about 10 μm, wherein the offset distance ismeasured along a longitudinal axis of the at least one microneedle.

Embodiment I-24. The microneedle array of embodiment I-1, wherein theelectrode is annular.

Embodiment I-25. The microneedle array of embodiment I-1, wherein aportion of the working electrode is recessed into the tapered distalportion.

Embodiment I-26. The microneedle array of embodiment I-1, wherein theelectrode is on only a segment of the tapered distal portion.

Embodiment I-27. The microneedle array of embodiment I-1, furthercomprising an electrical contact, wherein the at least one microneedlecomprises a body portion providing a conductive pathway between theelectrical contact and the electrode.

Embodiment I-28. The microneedle array of embodiment I-27, wherein thebody portion is formed from a conductive material.

Embodiment I-29. The microneedle array of embodiment I-27, wherein thebody portion comprises an embedded pathway.

Embodiment I-30. The microneedle array of embodiment I-27, wherein thebody portion is insulated.

Embodiment I-31. The microneedle array of embodiment I-27, wherein thebody portion has a circular, square, or an octagonal base.

Embodiment I-32. The microneedle array of embodiment I-27, wherein atleast a segment of the body portion is columnar.

Embodiment I-33. The microneedle array of embodiment I-27, wherein atleast a segment of the body portion is pyramidal.

Embodiment I-34. The microneedle array of embodiment I-33, wherein atleast a portion of the body portion has a first taper angle measuredrelative to a base of the body portion and the distal apex has a secondtaper angle measured relative to the base, wherein the second taperangle is greater than the first taper angle.

Embodiment I-35. The microneedle array of embodiment I-34, wherein atleast one of the body portion and the distal portion of the microneedleis radially asymmetric.

Embodiment I-36. The microneedle array of embodiment I-35, wherein thetapered distal portion comprises a planar surface that is offset fromthe distal apex of the at least one microneedle.

Embodiment I-37. The microneedle array of embodiment I-1, wherein eachof the microneedles in the plurality of microneedles comprises a

-   -   a tapered distal portion having an insulated distal apex; and    -   an electrode on a surface of the tapered distal portion, wherein        the electrode is located proximal to the insulated distal apex.

Embodiment I-38. The microneedle array of embodiment I-1, wherein themicroneedles of the plurality of microneedles are electrically insulatedfrom one another.

Embodiment I-39. The microneedle array of embodiment I-38, wherein themicroneedle array is configured to detect multiple analytes.

Embodiment I-40. The microneedle array of embodiment I-1, wherein themicroneedles of the plurality of microneedles are arranged in a periodicgrid.

Embodiment I-41. The microneedle array of embodiment I-40, wherein theperiodic grid comprises a rectangular array.

Embodiment I-42. The microneedle array of embodiment I-40, wherein theperiodic grid comprises a hexagonal array.

Embodiment I-43. The microneedle array of embodiment I-40, wherein themicroneedles in the periodic grid are spaced apart by a distance betweenabout 200 μm and about 800 μm.

Embodiment I-44. The microneedle array of embodiment I-40, wherein themicroneedles in the periodic grid are uniformly spaced apart.

Embodiment I-45. The microneedle array of embodiment I-1, wherein theplurality of microneedles comprises at least one delivery microneedlewith a lumen.

Embodiment I-46. The microneedle array of embodiment I-1, wherein the atleast one microneedle is configured to puncture skin of a user and sensean analyte in interstitial fluid in a dermal layer of the user.

Embodiment I-47. An analyte monitoring system comprising the microneedlearray of embodiment I-1 and a wearable housing, wherein the microneedlearray extends outwardly from the housing.

Embodiment I-48. The system of embodiment I-47, wherein the at least onemicroneedle extends from the housing such that a distal end of theelectrode is located less than about 5 mm from the housing.

Embodiment I-49. The system of embodiment I-48, wherein the at least onemicroneedle extends from the housing such that the distal end of theelectrode is located less than about 1 mm from the housing.

Embodiment I-50. The system of embodiment I-47, wherein the housingencloses an electronics system comprising at least one of a processorand a wireless communication module.

Embodiment I-51. The system of embodiment I-50, wherein the electronicssystem comprises a wireless communication module and the system furthercomprises a software application executable on a mobile computing deviceto be paired with the wireless communication module.

Embodiment I-52. The system of embodiment I-47, wherein the housingcomprises one or more indicator lights configured to communicate statusinformation.

Embodiment I-53. The system of embodiment I-52, wherein at least one ofthe indicator lights is configured to be selectively illuminated inaccordance with an illumination mode corresponding to an analytemeasurement status.

Embodiment I-54. The system of embodiment I-53, wherein at least one ofthe indicator lights is configured to be selectively illuminated tocommunicate a current analyte measurement level.

Embodiment I-55. The system of embodiment I-53, wherein the userinterface comprises a plurality of indicator lights configured to beselectively illuminated in a progressive sequence to communicate ananalyte measurement trend.

Embodiment I-56. The system of embodiment I-55, wherein the plurality ofindicator lights is configured to be selectively illuminated in a firstprogressive sequence in a first direction to communicate a risinganalyte measurement trend, and is further configured to be selectivelyilluminated in a second progressive sequence in a second direction tocommunicate a falling analyte measurement trend.

Embodiment I-57. The system of embodiment I-52, wherein the userinterface is further configured to communicate information indicative ofa status of the analyte monitoring device.

Embodiment I-58. The system of embodiment I-47, further comprising anadhesive configured to couple the housing to the skin of a user.

Embodiment I-59. The system of embodiment I-47, further comprising anapplicator configured to apply the at least a portion of the analytemonitoring system to the skin of a user.

Embodiment I-60. The system of embodiment I-47, wherein the analytemonitoring system is a skin-adhered patch.

Embodiment I-61. The system of embodiment I-47, wherein the plurality ofmicroneedles comprises at least one delivery microneedle with a lumen.

Embodiment I-62. The system of embodiment I-47, wherein the plurality ofmicroneedles comprises at least one solid microneedle comprising acoating comprising a therapeutic substance.

Embodiment I-63. The system of embodiment I-62, wherein the therapeuticsubstance comprises at least one of insulin, glucagon, metformin,acetaminophen, acetylsalicylic acid, isobutylphenylpropionic acid,levodopa, a statin, a hydrocodone, an opioid, a non-steroidalanti-inflammatory, an anesthetic, an analgesic, an anticonvulsant, anantidepressant, an antipsychotic, a sedative, a relaxant, a hormonalagent, an antibacterial agent, and an antiviral agent.

Embodiment I-64. A method for monitoring a user, comprising:

-   -   accessing a body fluid of the user with an analyte monitoring        device; and    -   quantifying one or more analytes in the body fluid using the        analyte monitoring device,    -   wherein the analyte monitoring device comprises a plurality of        solid microneedles, wherein at least one microneedle comprises:        -   a tapered distal portion having an insulated distal apex;            and        -   an electrode on a surface of the tapered distal portion,            wherein the electrode is located proximal to the insulated            distal apex.

Embodiment I-65. The method of embodiment I-64, wherein the body fluidcomprises a dermal interstitial fluid of the user.

Embodiment I-66. The method of embodiment I-64, wherein the one or moreanalytes comprises glucose.

Embodiment I-67. A microneedle array for use in sensing an analyte,comprising:

-   -   a plurality of solid microneedles, wherein at least one        microneedle comprises:    -   a tapered distal portion having an insulated distal apex; and    -   an electrode on a surface of the tapered distal portion, wherein        a distal end of the electrode is offset from the distal apex.

Embodiment I-68. The microneedle array of embodiment I-67, wherein theelectrode is a working electrode configured to sense at least oneanalyte and the at least one microneedle comprises a biorecognitionlayer arranged over the working electrode, wherein the biorecognitionlayer comprises a biorecognition element.

Embodiment I-69. The microneedle array of embodiment I-68, wherein thebiorecognition element comprises glucose oxidase.

Embodiment I-70. The microneedle array of embodiment I-67, wherein thedistal end of the electrode is offset from the distal apex by an offsetdistance of at least about 10 μm, wherein the offset distance ismeasured along a longitudinal axis of the at least one microneedle.

Embodiment I-71. The microneedle array of embodiment I-67, wherein theelectrode is annular.

Embodiment I-72. The microneedle array of embodiment I-67, wherein in atleast one microneedle, a portion of the working electrode is recessedinto the tapered distal portion.

Embodiment I-73. The microneedle array of embodiment I-67, wherein theelectrode is on only a segment of the tapered distal portion.

Embodiment I-74. The microneedle array of embodiment I-67, furthercomprising an electrical contact, wherein the at least one microneedlecomprises a body portion providing a conductive pathway between theelectrical contact and the electrode.

Embodiment I-75. The microneedle array of embodiment I-67, wherein eachof the microneedles in the plurality of microneedles comprises a

-   -   a tapered distal portion having an insulated distal apex; and    -   an electrode on a surface of the tapered distal portion, wherein        the electrode is located proximal to the insulated distal apex.

Embodiment I-76. The microneedle array of embodiment I-67, wherein themicroneedle array comprises a plurality of working electrodes, whereineach working electrode is individually addressable and electricallyisolated from every other working electrode in the analyte monitoringdevice.

Embodiment I-77. The microneedle array of embodiment I-76, wherein themicroneedle array is configured to detect multiple analytes.

Embodiment I-78. The microneedle array of embodiment I-67, wherein themicroneedles of the plurality of microneedles are arranged in ahexagonal array.

Embodiment I-79. The microneedle array of embodiment I-67, wherein theat least one microneedle is configured to puncture skin of a user andsense an analyte in interstitial fluid in a dermal layer of the user.

Embodiment I-80. An analyte monitoring system comprising the microneedlearray of embodiment I-67 and a wearable housing, wherein the microneedlearray extends outwardly from the housing.

Embodiment I-81. The system of embodiment I-80, wherein the at least onemicroneedle extends from the housing such that the distal end of theelectrode is located less than about 5 mm from the housing.

Embodiment I-82. The system of embodiment I-80, wherein the housingencloses an electronics system comprising a wireless communicationmodule and the system further comprises a software applicationexecutable on a mobile computing device to be paired with the wirelesscommunication module.

Embodiment I-83. The system of embodiment I-80, wherein the housingcomprises a user interface comprising one or more indicator lightsconfigured to communicate status information.

Embodiment I-84. The system of embodiment I-83, wherein at least one ofthe indicator lights is configured to be selectively illuminated inaccordance with an illumination mode corresponding to an analytemeasurement status.

Embodiment I-85. The system of embodiment I-83, wherein the analytemonitoring system comprises a skin-adhered patch.

Embodiment I-86. A method of sterilizing an analyte monitoring device,the method comprising:

-   -   exposing the analyte monitoring device to a sterilant gas,        wherein the analyte monitoring device comprises a wearable        housing, a microneedle array extending from the housing and        comprising an analyte sensor, and an electronics system arranged        in the housing and electrically coupled to the microneedle        array,    -   wherein the analyte monitoring device is exposed to the        sterilant gas for a dwell time sufficient to sterilize the        analyte monitoring device.

Embodiment I-87. The method of embodiment I-86, wherein the sterilantgas is suitable for oxidative sterilization.

Embodiment I-88. The method of embodiment I-87, wherein the sterilantgas comprises ethylene oxide.

Embodiment I-89. The method of embodiment I-86, wherein the analytesensor comprises an electrode.

Embodiment I-90. The method of embodiment I-89, wherein the analytesensor comprises a biorecognition layer arranged over the electrode,wherein the biorecognition layer comprises a biorecognition element.

Embodiment I-91. The method of embodiment I-90, wherein thebiorecognition element comprises an enzyme.

Embodiment I-92. The method of embodiment I-91, wherein the enzyme is anoxidoreductase.

Embodiment I-93. The method of embodiment I-92, wherein theoxidoreductase is at least one of lactate oxidase, alcohol oxidase,beta-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbateoxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, urateoxidase, urease, and xanthine oxidase.

Embodiment I-94. The method of embodiment I-92, wherein theoxidoreductase is glucose oxidase.

Embodiment I-95. The method of embodiment I-90, wherein thebiorecognition element is cross-linked with an amine-condensing carbonylchemical species.

Embodiment I-96. The method of embodiment I-95, wherein theamine-condensing carbonyl chemical species is at least one offormaldehyde, glyoxal, malonaldehyde, and succinaldehyde.

Embodiment I-97. The method of embodiment I-95, wherein theamine-condensing carbonyl chemical species is glutaraldehyde.

Embodiment I-98. The method of embodiment I-90, wherein thebiorecognition layer is formed at least in part by cross-linking thebiorecognition element to form cross-linked biorecognition elementaggregates, and embedding the cross-linked biorecognition elementaggregates in a conducting polymer.

Embodiment I-99. The method of embodiment I-98, wherein embedding thecross-linked biorecognition element aggregates comprises embedding onlycross-linked biorecognition element aggregates having at least athreshold molecular weight.

Embodiment I-100. The method of embodiment I-86, wherein exposing theanalyte monitoring device to the sterilant gas comprises injecting thesterilant gas into a compartment containing the analyte monitoringdevice, and heating the compartment to a sterilization temperature.

Embodiment I-101. The method of embodiment I-100, wherein thesterilization temperature is below about 45 degrees Celsius and thedwell time is at least about 2 hours.

Embodiment I-102. The method of embodiment I-86, further comprisingpreconditioning the analyte monitoring device prior to exposing theanalyte monitoring device to the sterilant gas, wherein preconditioningthe analyte comprises exposing the analyte monitoring device to steam.

Embodiment I-103. A microneedle array for an analyte monitoring device,the microneedle array comprising:

-   -   a plurality of solid sensing microneedles, wherein each sensing        microneedle comprises:    -   a tapered distal portion comprising a working electrode        configured to sense an analyte; and    -   a body portion providing a conductive connection to the working        electrode,    -   wherein the body portion of each sensing microneedle is        insulated such that each working electrode is individually        addressable and electrically isolated from every other working        electrode in the microneedle array.

Embodiment I-104. The microneedle array of embodiment I-103, wherein atleast one sensing microneedle comprises a biorecognition layer arrangedover the working electrode, wherein the biorecognition layer comprises abiorecognition element.

Embodiment I-105. The microneedle array of embodiment I-104, wherein thebiorecognition element comprises an enzyme.

Embodiment I-106. The microneedle array of embodiment I-105, wherein theenzyme is an oxidoreductase.

Embodiment I-107. The microneedle array of embodiment I-106, wherein theoxidoreductase is at least one of lactate oxidase, alcohol oxidase,beta-hydroxybutyrate dehydrogenase, tyrosinase, catalase, ascorbateoxidase, cholesterol oxidase, choline oxidase, pyruvate oxidase, urateoxidase, urease, and xanthine oxidase.

Embodiment I-108. The microneedle array of embodiment I-106, wherein theoxidoreductase is glucose oxidase.

Embodiment I-109. The microneedle array of embodiment I-104, wherein thebiorecognition element is cross-linked with an amine-condensing carbonylchemical species.

Embodiment I-110. The microneedle array of embodiment I-109, wherein theamine-condensing carbonyl chemical species is at least one offormaldehyde, glyoxal, malonaldehyde, and succinaldehyde.

Embodiment I-111. The microneedle array of embodiment I-109, wherein theamine-condensing carbonyl chemical species is glutaraldehyde.

Embodiment I-112. The microneedle array of embodiment I-104, wherein theat least one sensing microneedle comprises at least one of adiffusion-limiting layer and a hydrophilic layer arranged over thebiorecognition layer.

Embodiment I-113. The microneedle array of embodiment I-103, wherein themicroneedle array further comprises at least one microneedle comprisinga counter electrode configured to source or sink current to sustain anelectrochemical reaction on the working electrode of at least onesensing microneedle.

Embodiment I-114. The microneedle array of embodiment I-103, wherein theplurality of microneedles comprises at least one microneedle comprisinga reference electrode configured to provide a reference potential forthe working electrode.

Embodiment I-115. The microneedle array of embodiment I-114, furthercomprising a conducting polymer arranged over the reference electrode.

Embodiment I-116. The microneedle array of embodiment I-115, wherein theconducting polymer comprises a dopant.

Embodiment I-117. The microneedle array of embodiment I-114, wherein thereference electrode comprises a metal oxide with a stable electrodepotential.

Embodiment I-118. The microneedle array of embodiment I-117, wherein themetal oxide comprises iridium oxide.

Embodiment I-119. The microneedle array of embodiment I-114, wherein thereference electrode comprises a metal salt with a stable electrodepotential.

Embodiment I-120. The microneedle array of embodiment I-119, wherein themetal salt comprises silver chloride.

Embodiment I-121. The microneedle array of embodiment I-103, wherein inat least one sensing microneedle, the tapered distal portion comprisesan insulated distal apex and the working electrode is proximal to theinsulated distal apex.

Embodiment I-122. The microneedle array of embodiment I-121, wherein adistal end of the working electrode is offset from the distal apex by anoffset distance of at least about 10 μm, wherein the offset distance ismeasured along a longitudinal axis of the at least one sensingmicroneedle.

Embodiment I-123. The microneedle array of embodiment I-103, wherein inat least one sensing microneedle, a portion of the working electrode isrecessed into the tapered distal portion.

Embodiment I-124. An analyte monitoring device comprising themicroneedle array of embodiment I-103 and a wearable housing, whereinthe microneedle array extends outwardly from the housing.

Embodiment I-125. The analyte monitoring device of embodiment I-124,wherein the housing comprises one or more indicator lights configured tocommunicate status information.

Embodiment I-126. The analyte monitoring device of embodiment I-124,wherein the housing encloses an electronics system comprising at leastone of a processor and a wireless communication module.

Embodiment I-127. The analyte monitoring device of embodiment I-126,wherein the analyte monitoring device is a skin-adhered patch.

Embodiment I-128. A microneedle array for a body-worn analyte monitoringdevice, wherein the microneedle array comprises:

-   -   at least one microneedle comprising:    -   a pyramidal body portion having a non-circular base; and    -   a tapered distal portion extending from the body portion and        comprising an electrode,    -   wherein the distal portion comprises a planar surface that is        offset from a distal apex of the at least one microneedle.

Embodiment I-129. The microneedle array of embodiment I-128, wherein atleast a portion of the body portion has a first taper angle measuredrelative to the base and the distal apex has a second taper anglemeasured relative to the base, wherein the second taper angle is greaterthan the first taper angle.

Embodiment I-130. The microneedle array of embodiment I-128, wherein thesecond taper is between about 65 degrees and about 75 degrees.

Embodiment I-131. The microneedle array of embodiment I-130, wherein thefirst taper is between about 15 degrees and about 25 degrees.

Embodiment I-132. The microneedle array of embodiment I-128, wherein theplanar surface is angled between about 75 degrees and 85 degreesmeasured relative to the base.

Embodiment I-133. The microneedle array of embodiment I-128, wherein thetapered distal portion comprises an insulated distal apex.

Embodiment I-134. An analyte monitoring device comprising themicroneedle array of embodiment I-128 and a wearable housing, whereinthe microneedle array is configurable to extend outwardly from thehousing.

Embodiment I-135. The analyte monitoring device of embodiment I-134,wherein the analyte monitoring device is a patch.

Embodiment I-136. A method for monitoring a user, comprising:

-   -   accessing a dermal interstitial fluid of the user at a plurality        of sensor locations with an integrated analyte monitoring device        comprising a single microneedle array;    -   quantifying one or more analytes in the dermal interstitial        fluid using a plurality of working electrodes in the microneedle        array, wherein each working electrode is individually        addressable and electrically isolated from every other working        electrode in the analyte monitoring device.

Embodiment I-137. The method of embodiment I-136, wherein quantifyingone or more analytes comprises quantifying a plurality of analytes inthe dermal interstitial fluid using the plurality of working electrodes.

Embodiment I-138. The method of embodiment I-136, wherein themicroneedle array comprises a plurality of sensing microneedles, eachsensing microneedle comprising a respective working electrode.

Embodiment I-139. The method of embodiment I-138, wherein at least onesensing microneedle comprises a biorecognition layer arranged over theworking electrode, wherein the biorecognition layer comprises an enzyme.

Embodiment I-140. The method of embodiment I-139, wherein the at leastone microneedle comprises at least one of a diffusion-limiting layer anda hydrophilic layer arranged over the biorecognition layer.

Embodiment I-141. The method of embodiment I-136, wherein themicroneedle array comprises at least one microneedle comprising acounter electrode configured to source or sink current to sustain anelectrochemical reaction on at least one working electrode.

Embodiment I-142. The method of embodiment I-136, wherein the pluralityof microneedles comprises at least one microneedle comprising areference electrode configured to provide a reference potential for atleast one working electrode.

Embodiment I-143. The method of embodiment I-142, further comprising aconducting polymer arranged over the reference electrode.

Embodiment I-144. The method of embodiment I-143, wherein the conductingpolymer comprises a dopant.

Embodiment I-145. The method of embodiment I-142, wherein the referenceelectrode comprises a metal oxide with a stable electrode potential.

Embodiment I-146. The method of embodiment I-145, wherein the metaloxide comprises iridium oxide.

Embodiment I-147. The method of embodiment I-142, wherein the referenceelectrode comprises a metal salt with a stable electrode potential.

Embodiment I-148. The method of embodiment I-147, wherein the metal saltcomprises silver chloride.

Embodiment I-149. The method of embodiment I-136, further comprisingcommunicating status information indicative of the quantification of theone or more analytes.

Embodiment I-150. The method of embodiment I-149, wherein themicroneedle array extends outwardly from a wearable housing andcommunicating status information comprises communicating statusinformation via a user interface on the housing.

Embodiment I-151. The method of embodiment I-150, wherein communicatingstatus information comprises selectively illuminating one or moreindicator lights on the housing in accordance with an illumination modecorresponding to an analyte measurement status or a status of theintegrated analyte monitoring device.

Embodiment I-152. The method of embodiment I-150, wherein communicatingstatus information comprises activating a display corresponding to ananalyte measurement status or a status of the integrated analytemonitoring device.

Embodiment I-153. A body-worn analyte monitoring device, comprising:

-   -   a wearable housing; and    -   a microneedle array extending outwardly from the housing and        comprising at least one microneedle configured to measure one or        more analytes in a user wearing the housing, wherein the housing        comprises a user interface configured to communicate information        indicative of the measurement of the one or more analytes.

Embodiment I-154. The device of embodiment I-153, wherein the userinterface comprises one or more indicator lights configured to beselectively illuminated in accordance with an illumination modecorresponding to an analyte measurement status or a status of anintegrated analyte monitoring device.

Embodiment I-155. The device of embodiment I-154, wherein at least oneof the indicator lights is configured to be selectively illuminated tocommunicate a current analyte measurement level.

Embodiment I-156. The device of embodiment I-154, wherein the userinterface comprises a plurality of indicator lights configured to beselectively illuminated in a progressive sequence to communicate ananalyte measurement trend.

Embodiment I-157. The device of embodiment I-156, wherein the pluralityof indicator lights is configured to be selectively illuminated in afirst progressive sequence in a first direction to communicate a risinganalyte measurement trend.

Embodiment I-158. The device of embodiment I-156, wherein the pluralityof indicator lights is configured to be selectively illuminated in asecond progressive sequence in a second direction to communicate afalling analyte measurement trend.

Embodiment I-159. The device of embodiment I-153, wherein the userinterface is further configured to communicate information indicative ofa status of the analyte monitoring device.

Embodiment I-160. The device of embodiment I-153, wherein the userinterface comprises a display screen.

Embodiment I-161. The device of embodiment I-153, wherein the analytemonitoring device is a skin-adhered patch.

Embodiment I-162. The device of embodiment I-153, wherein the at leastone microneedle comprises a tapered distal portion with an insulateddistal apex, and an electrode on a surface of the tapered distalportion, wherein the electrode is located proximal to the insulateddistal apex.

Embodiment I-163. The device of embodiment I-153, wherein themicroneedle array comprises a plurality of working electrodes, whereineach working electrode is individually addressable and electricallyisolated from every other working electrode in the analyte monitoringdevice.

Embodiment I-164. A method for monitoring a user, comprising:

-   -   measuring one or more analytes in the user using a body-worn        analyte monitoring device comprising a wearable housing and one        or more analyte sensors;    -   communicating information indicative of the measurement of the        one or more analytes through a user interface on the housing.

Embodiment I-165. The method of embodiment I-164, wherein communicatinginformation comprises illuminating one or more indicator lights on thehousing in accordance with an illumination mode corresponding to ananalyte measurement status.

Embodiment I-166. The method of embodiment I-165, wherein communicatinginformation comprises selectively illuminating at least one of theindicator lights to communicate a current analyte measurement level.

Embodiment I-167. The method of embodiment I-166, wherein communicatinginformation comprises communicating the current analyte measurementlevel based on color of the illuminated indicator light, location of theilluminated indicator light, or both.

Embodiment I-168. The method of embodiment I-165, wherein communicatinginformation comprises selectively illuminating a plurality of indicatorlights on the housing in a progressive sequence to communicate ananalyte measurement trend.

Embodiment I-169. The method of embodiment I-168, wherein communicatinginformation comprises selectively illuminating the plurality ofindicator lights in a first progressive sequence in a first direction tocommunicate a rising analyte measurement trend.

Embodiment I-170. The method of embodiment I-168, wherein communicatinginformation comprises selectively illuminating the plurality ofindicator lights in a second progressive sequence in a second directionto communicate a falling analyte measurement trend.

Embodiment I-171. The method of embodiment I-164, further comprisingcommunicating information indicative of a status of the analytemonitoring device through the user interface.

Embodiment I-172. The method of embodiment I-164, further comprisingaccessing a dermal interstitial fluid of the user at a plurality ofsensor locations with the analyte monitoring device, wherein quantifyingone of more analytes comprises quantifying one or more analytes in thedermal interstitial fluid.

Embodiment I-173. The method of embodiment I-164, wherein the analytemonitoring device comprises a microneedle array comprising a pluralityof working electrodes, wherein each working electrode is individuallyaddressable and electrically isolated from every other working electrodein the analyte monitoring device.

The foregoing description, for purposes of explanation, used specificnomenclature to provide a thorough understanding of the invention.However, it will be apparent to one skilled in the art that specificdetails are not required in order to practice the invention. Thus, theforegoing descriptions of specific embodiments of the invention arepresented for purposes of illustration and description. They are notintended to be exhaustive or to limit the invention to the precise formsdisclosed; obviously, many modifications and variations are possible inview of the above teachings. The embodiments were chosen and describedin order to explain the principles of the invention and its practicalapplications, they thereby enable others skilled in the art to utilizethe invention and various embodiments with various modifications as aresuited to the particular use contemplated. It is intended that thefollowing claims and their equivalents define the scope of theinvention.

The invention claimed is:
 1. A microneedle array for use in sensing ananalyte, comprising: a semiconductor substrate; a plurality of solidmicroneedles extending from the substrate, wherein at least onemicroneedle of the plurality of microneedles is configured to sense ananalyte in dermal interstitial fluid of a user and comprises: a columnarbody portion; a tapered distal portion having an insulated distal apex;and an annular working electrode coupled to a surface of the tapereddistal portion, wherein a portion of the working electrode overlies andextends beyond an annular recess formed in the surface of the tapereddistal portion, wherein the working electrode extends onto the surfaceof the tapered distal portion on each side of the annular recess.
 2. Themicroneedle array of claim 1, wherein the tapered distal portion isdistal to the columnar body portion.
 3. The microneedle array of claim1, wherein the working electrode comprises a proximal edge and a distaledge and is on only a segment of the surface of the tapered distalportion of the microneedle.
 4. The microneedle array of claim 3, whereinthe distal edge of the working electrode is distal to a proximal edge ofthe insulated distal apex.
 5. The microneedle array of claim 1, whereinthe at least one microneedle comprises a biorecognition layer arrangedover the working electrode, wherein the biorecognition layer comprises abiorecognition element.
 6. The microneedle array of claim 5, wherein thebiorecognition element comprises glucose oxidase.
 7. The microneedlearray of claim 1, wherein the microneedle array further comprises atleast one microneedle comprising a counter electrode configured tosource or sink current to sustain an electrochemical reaction on theworking electrode.
 8. The microneedle array of claim 1, wherein themicroneedle array further comprises at least one microneedle comprisinga reference electrode configured to provide a reference potential forthe working electrode.
 9. The microneedle array of claim 3, wherein thedistal edge of the working electrode is offset from the insulated distalapex by an offset distance of at least about 10 μm, wherein the offsetdistance is measured along a longitudinal axis of the at least onemicroneedle.
 10. The microneedle array of claim 1, further comprising anelectrical contact on a backside of the substrate, wherein the columnarbody portion of the at least one microneedle of the plurality ofmicroneedles provides a conductive pathway between the electricalcontact and the working electrode.
 11. The microneedle array of claim10, wherein the columnar body portion is formed from a conductivematerial.
 12. The microneedle array of claim 10, wherein the columnarbody portion comprises an embedded conductive pathway.
 13. Themicroneedle array of claim 10, wherein the columnar body portion isinsulated.
 14. The microneedle array of claim 1, further comprising abiorecognition layer arranged over the working electrode extending ontothe surface of the tapered distal portion.
 15. The microneedle array ofclaim 1, wherein the at least one microneedle comprises only one annularworking electrode.
 16. The microneedle array of claim 1, wherein each ofthe microneedles in the plurality of solid microneedles comprises: acolumnar body portion; a tapered distal portion having an insulateddistal apex; and an annular electrode on a surface of the tapered distalportion, wherein the annular electrode is proximate a proximal edge ofthe insulated distal apex, and wherein the annular electrode is aworking electrode, a counter electrode, or a reference electrode. 17.The microneedle array of claim 1, wherein the microneedle arraycomprises a plurality of working electrodes, wherein each workingelectrode is individually addressable and electrically isolated fromevery other working electrode in the microneedle array.
 18. Themicroneedle array of claim 17, wherein the microneedle array isconfigured to detect multiple analytes.
 19. The microneedle array ofclaim 1, wherein the plurality of solid microneedles are arranged in asquare or hexagonal array.
 20. An analyte monitoring system comprising:an analyte monitoring device comprising: the microneedle array of claim1; and a wearable housing, wherein the microneedle array extendsoutwardly from the housing.
 21. The system of claim 20, wherein the atleast one microneedle of the plurality of microneedles extends from thewearable housing such that the distal end of the working electrode islocated less than about 1 mm from the wearable housing.
 22. The systemof claim 20, wherein the wearable housing encloses an electronics systemcomprising a wireless communication module and the system furthercomprises a software application executable on a mobile computing deviceto be paired with the wireless communication module.
 23. The system ofclaim 20, wherein the housing comprises a user interface comprising oneor more indicator lights configured to communicate status information.24. The system of claim 23, wherein at least one of the indicator lightsis configured to be selectively illuminated in accordance with anillumination mode corresponding to an analyte measurement status, astatus of the analyte monitoring device, or both.
 25. The system ofclaim 24, wherein at least one of the indicator lights is configured tobe selectively illuminated to communicate a current analyte measurementlevel.
 26. The system of claim 23, wherein the user interface is furtherconfigured to communicate information indicative of a status of theanalyte monitoring device.
 27. The system of claim 20, wherein theanalyte monitoring device is a skin-adherable patch.